SA08290043B1 - New Tricyclic Compounds, a Process for Their Preparation and Pharmaceutical Compositions Containing Them for Treatment of Cancer - Google Patents

Abstract

Abstract The present invention relates to compounds having the formula (I): where: A is a hetero-aromatic or non-aromatic ring consisting of 5, 6, or 7 atoms, n and n' representing zero, or 1, or 2, X represents an alkylene chain as defined in the Specification, R3 represents an aryl group or heteroaryl, one of the R1 and R2 groups represents a hydrogen atom and the other represents a group of formula (II) as defined in the Specification.

Description

new tricyclic compounds; New Tricyclic Compounds, a Process for Their Preparation and Pharmaceutical ‎Compositions Containing Them for Treatment of Cancer Full Description Background The present invention relates to new tricyclic compounds and a process for their preparation; And pharmaceutical formulations containing it. The compounds of the present invention are novel and have highly valuable pharmacological profiles in the field of WAY and cancer studies. Cell death or programmed cell death is an important physiological process in the development of the embryo and the maintenance of homogeneous stability of tissues. Cell death causes Jha changes, nucleus condensation (AICS), DNA fragmentation, and biochemical phenomena, such as: activation of caspases that damage major structural components of the cell, causing induction Jala cell (2002, 2, 647-656 - Cory 5. et ah, Nature Review Cancer, Disorders are Disturbances that occur in the process of cell death are involved in certain diseases.The processes of excess cell death are associated with neurodegenerative diseases, such as: Parkinson's disease 0 », Alzheimer's disease, and localized insufficiency.

y — _— opposite; Differences in the execution of cell death play a role (Unga) in the development of cancers, Ler-specific chemoresistance, auto-immune diseases, inflammatory diseases, and viral infections. infections © and accordingly; The absence of cell death is one of the characteristic signals related to the cancer phenotype: -(Hanahan D. et ah, Cell 2000, 1 00, 57-70) General description of the invention Compounds of the present invention include; In addition to being new; It has pro-apoptotic properties, which means it can be used in diseases in which there are deficiencies in LDA apoptosis, for example in the treatment of cancer. The present invention relates more specifically to a compound of formula (): Ra R; A N J In’ ( n N - 1 “ks Yay

— p_ where: A is an aromatic (heterocyclic) or non-aromatic ring formed by ©; or aay Ja can contain 1 or ? Of the selected heterogeneous atoms of oxygen » and sulfur nitrogen ; It is possible for the latter to be replaced by a straight or branched (and©-0) alkyl group; 0 and it is understood that ring A so defined cannot contain Y a sulfur ¢ atom or

An oxygen atom and one of the ring atoms can be a set 'C=0 n and 12 can be the same or different and represent zero 6 or 1 ¢ or Y ' where zero > 1 + 11 > 4 '

« heteroaryl or heteroaryl aryl representing the group Ry

X is an alkylene chain containing from 1 to a SHIT carbon; One or two of them can be replaced

0 carbon atoms of an oxygen atom “arylene dc sana 0 group” cycloalkylene “heteroaryl ¢ group arylene” or “SO” group; it represents one of the two Ry groups and 82 hydrogen atoms and it has J of another is a group of formula (I) an Rs NH 1 m b Ry where: Jia Y —- Yo group C=0 or “CH,

— uh - Rs - stands for 5,0 hydrogen where in this case it stands for hydrogen 5,0 Rg or combination 11127187 or 0111-2087877- where both 187 and 87 can be the same or different; It is represented independently of the other components 3) 3 hydrogen or an alkyl group (C-Cs) substituted with one or the iS of the aryl groups » or heteroaryl heteroaryl « i.e. heteroaryloxy sl 0 aryloxy © « or arylthio ¢ or heteroarylthio » or heterocycloalkyl or m INR, where selectable b R'jo which can be congruent or different; of hydrogen « or alkyl (C1-C) straight or branched or (©-©) asia alkoxy or branched; aryl » heteroaryl » or Ryo and 18:0 can form an unsaturated cyclic or dicyclic group can have a selected heteroaryl atom substituted from nitrogen 5 « oxygen ; and sulfur ¢ and it is realized that 0 -one or more of the atoms can represent the 0-0 group; or it may have a substitution as shown in the definition of heterocycloalkyl shown below; or Res Rs with their carbon atoms form an aromatic or non-aromatic ring containing © or “cyclic atoms; and one nitrogen atom being at position para of group :50; which may contain - in addition to a nitrogen atom - has an additional nitrogen atom and/or “SO; Yo” group and the ring thus defined has a substitution of an :8 group as defined above; R, - represents a halogen atom or ( NO, or Rs or «803-Ry or (m©-,©) adie alkyl or branched; or (©-©) aii alkoxy or branched; where Ry can have Any of the values of 8 as defined above; -y represents an amino group or a group (0-,0) a straight or branched alkyl having an arbitrary 0 substitution by one or more halogen atoms « 7s

It is understood that: biphenyl sf » naphthyl Ji « phenyl ic ses "aryl" - « - "heteroaryl aryl heteroaryl means a monocyclic or dicyclic group comprising at least one aromatic moiety and containing from * to 0 atoms; and may To include from 1 to selected heteroatoms of oxygen and sulfur nitrogen + sulfur such as: groups: furan, thiophene, pyrrole, imidazoline, pyridine, quinoline, isoquinoline, chroman, indole, benzothiophene , benzofuran, 1,3-benzodioxole and 2,3-dihydro-1,4- benzodioxine heterocycloalkyl' - "means a monocyclic or bicyclic group comprising of; to 10 atoms; which 0 can include from 1 to ? Selected heteroatoms of oxygen ; and sulfur ¢ nitrogen ¢ cycloalkyl" - "means a monocyclic or bicyclic group comprising of; to 10 atoms; It is possible for aryl and hetero-aryl groups; heterocycloalkyl ¢ and cycloalkyl which are defined to have from 1 to ¥ substitution of select groups from a VO group (the ©0-©) straight or branched alkyl group having an optionally substituted with a hydroxy group or amino or alkoxy group (C)-Cs) straight or concave; hydroxy sf ¢ or formyl 4 « carboxy ; or cyano sl “nitro” or amino “+ or combination (and©-) straight or concave polyhalo; alkoxycarbonyl and halogen atoms »

) 0 - arylene' »" arylene' - heterocyclic" 5 cycloalkylene ' ' means; respectively; group aryl + or heteroaryl « ie cycloalkyl as defined before; Ya is incorporated from a carbon atom of the alkylene chain “its enantiomers and diastereoisomers” and addition salts thereof with a pharmaceutically acceptable acid or a pharmaceutically acceptable base. Among the pharmaceutically acceptable acids; It can be mentioned - for example: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphonic acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid, oxalic acid, methanesulphonic acid, camphoric acid and so on. Among the pharmaceutically acceptable bases can be mentioned - but not limited to: sodium hydroxide, potassium hydroxide, triethylamine, tert-butylamine ... etc. Yo It is useful that Y has a group C=0. The preferred value for '' is 1. dias. The preferred Ry groups are -SO,CF; 3 NO, Ole Ghana

A — — The preferred Ry groups are Les ([1,1-biphenyl]-2-yl)methyl groups optionally substituted with one or more of the selected cyano “halogen” groups and a 0 trifluoromethyl conjugate 4 « aminomethyl 4 preferably represents 0 hydrogen 3,3 Rs The preferred groups are: I-(N,N-dimethylam ino)-4-(phenylsulfanyl)-butan-3 -yl and 1-( NR10R'10)-4- (phenylsulfanyl)-butan-3 ~yl such that Rig and 80 form an unsaturated or dicyclic group with an optionally substituted heterocyclic atom of "oxygen", "nitrogen" and sulfur 0 sulfur Vee would be useful to represent 187 0 hydrogen atoms A N N J . ( In N "'N the preferred | group is a group more specifically the invention relates to compounds having the formula (1) being: N-({ (4aS,R)-3-[(4'-chloro-[ 1,1 “biphenyl]-2-yh)methyl]-2,3,4,4a,5, 6-hexahydro-1H- pyrazino[1,2-ajquinolin-8-yl} carbonyl)-4-( {(1R)-3 -(dimethylamino)-1- [(phenyl-

= sulphanyl)methyl]propyl am ino)-3-nitrobenzenesulphonami de,

N-({(4aS,R)-3-[(4'-chloro-[1,1'-b iphenyl]-2-yl)methyl]-2,3,4,4a,5 ,6-hexahydro- 1H-pyrazino[1,2-a]quinolin-8-yl} carbonyl)-4-({(1R)-3-(di methylamino)-1-{(phenyl-sulphanyl)methyl]propyl}am ino)- 3-nitrobenzenesu Iphonamide bistrifluoroacetate,

N-({(4aS,R)-3-[(4'-chloro-[1,1 -biphenyl]-3-yl)methyl]-2,3 -4,4a,5,6-hexahydro-1H- © pyrazino[1,2-a]quinolin-8-yl} carbonyl)-3-nitro-4-{[2-(phenylsulphanyl)ethyl]-amino} benzenesulphonamide,

N-({(4aS,R)-3-[(4'-chloro-[1,1'-bi phenyl]-3-yl)methyl]-2,3,4,4a,5 ,6-hexahydro- 1H-pyrazino[1,2-a]quinolin-8-yl} carbonyl)-3-nitro-4-{[2 -(phenylsulphanyl)ethyl]- amino} benzenesulphonamide hydrochloride, Ye L {(4aS,R) -3-[(4'-chloro-[1,1 -biphenyl]-4-yl)methyl]-2,3 ,4,4a,5,6-hexahydro-1H- pyrazino[1,2-a]quinolin -8-yl} carbonyl)-3-nitro-4-{2-(phenylsuIphanyl)ethyl]-amino} benzenesulphonami de,

N-({(4aS,R)-3 -[(4'-chloro-[1,1 -biphenyl]-4-yl)methyl]-2,3 ,4.,4a,5,6-hexahydro-1H - pyrazinof1,2-ajquinolin-8-yl} carbonyl)-3-nitro-4-{[2 -(phenylsulphanyl)- Yo ethyl] Jamino}benzenesulphonamide hydrochloride,

N-{[(4aS,R)-3-([1,1"-biph enyl]-2-ylmethyl)-2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2- a]quinolin-8-yl]carbonyl} -4-({(1R)-3-(dimethylamino)-1-[(phenyl-sulphanyl)methyl]jpropyl} amino)-3 -nitrobenzenesulphonamide,

N-{[(4aS,R)-3-([1,1'-b iphenyl]-2-ylmethyl)-2,3 :4,4a,5,6-hexahydro-1H -pyrazino[1,2- Ye. a]quinolin-8-yl]carbonyl }-4-({(1R)-3 -(dimethylamino)-1 -[(phenyl-)

- 1o-sulphanyl)methyl]propyl} amino)-3-nitrobenzenesulphonamide bis(hydrochloride),

N-{[(4aS,R)-3-(2-benzylbenzyl)-2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2 -a]-quinolin-8- yl]earbonyl }-3-nitro-4-{[2- (phenylsulfanyl)ethyljamino} benzene-sulphonamide,

N-{[(4aS,R)-3-(2-benzylbenzyl)-2,3,4,4a,5,6 -hexahydro-1H-pyrazino[1,2-a] -quinolin-§-yl]carbonyl }-3-nitro-4-{[2 -(phenylsulfanyl)ethyl]amino} benzene-su Iphonamide © hydrochloride, 3-nitro-N-({(4aS,R)-3-[2-(2 -phenylethyl) benzyl]-2,3,4,4a,5,6-hexahydro-1H-z pyrazino[1,2-a]quinolin-8-y1} carbonyl)-4-{ [2-(phenylsulphanyl)ethyl [amino]-benzenesulphonamide,

N-({(4aS,R)-3-[(4'-chloro-[1,1 -biphenyl]-2-yl)methyl]-2,3 ,4,4a,5,6-hexahydro-1H- ye byrazinG [1,2-a]quinolin-8-yl} carbonyl)-3-nitro-4-{ [2-(phenylsulphanyl)ethyl]-amino} benzenesulphonamide,

N-({(4aS,R)-3-[(4'-chloro-[1,1'- biphenyl]-2-yl)methyl]-2,3,4,4a,5 ,6-hexahydro-1H - pyrazino[1,2-a]quinolin-8-y1} carbonyl)-3-nitro-4-[(2-phenoxyethyl)amino]-benzenesulphonamide, Yo

N-{[(4aS,R)-3-([1,1'-b iphenyl]-2-ylmethyl)-2,3 4, 4a,5,6-hexahydro-1H-pyrazino-[1,2- a]quinolin-8-yl]carbonyl}-3-nitro-4- [(3-phenylpropyl)amino] benzene-sulphonamide, 4-[(2-anilinoethyl)amino]-N- {{(4aS,R)- 3-([1,1 -biphenyl]-2-ylmethyl)-2,3 ,4,4a,5,6- hexahydro-1H-pyrazino[1 ,2-aJquinolin-8-yl]carbonyl} -3-nitrobenzene -sulphonamide,

N-{[(4aS,R)-3-([1,1 “-biphenyl]-2-ylmethyl)-2,3 -4,4a,5,6-hexahydro-1 H-pyrazino-[1,2 - Ye. aJquinolin-8-yljcarbonyl}-4-{[3 -(dimethylamino)propyl][2-(ph enylsulphanyl)-

Yay

-11 ethylJamino}-3-nitrobenzenesulphonamide,

N-{[(4aS,R)-3-([1,1-b iphenyl]-2-ylmethyl)-2,3.4, 4a,5,6-hexahydro-1H-pyrazino-[1,2-ajquinolin- 8-yljcarbonyl}-4-{[3-(d imethylamino)propyl][2-(phenylsuIphanyl)- ethyl]Jamino} -3-nitrobenzenesulphonamide hydrochloride,

N-({(4aS,R)-3-[(4"-chloro-[1,1 “-biphenyl]-2-yl)methyl]-2,3,4 4a, 5,6-hexahydro-1H- 5 pyrazino[1,2-aJquinolin-8-yl} carbonyl)-4-{[3-(dimethylamino)propyl]amino}-3- nitrobenzenesulphonamide,

N-({(4aS,R)-3-[(4'-chloro-[1,1 ~biphenyl]-2-yl)methyl]-2,3,4,4a,5,6-hexahydro- 111 pyrazino [1,2-a]quinolin-8-yl} carbonyl)benzenesulphonamide, 4- { [(2-aminoethyl)(2-phenyl ethyl)amino]methyl}-N-({(4aS,R)-3-[ (4'-chloro-[1,1'- Vo biphenyl]-2-yl)methyl]-2,3,4,4a,5,6 -hexahydro-1H-pyrazino[1,2 -ajquinolin-8-yl } - carbonyl)benzenesulphonamide, 4-{[(2-aminoethyl)(2-phenyl ethyl)amino]methyl}-N-({(4aS, R)-3-[(4'-chloro-[1,1" - biphenyl]-2-yl)methyl]-2,3,4,4a, 5,6-hexahydro-1H-pyrazino[ 1 ,2-a]quinolin-8-yl} - carbonyl)benzenesulphonamide tris(trifluoroacetate), Yo

N-({(4aS,R)-3 -[(4'-chloro-[1,1 -biphenyl]-2-yl)methyl]-2,3,4,4a,5,6-hexahydro- 1H- pyrazino[1,2-a]quinolin-7-yl jcarbonyl)-4-({(1R)-3-(di methylamino)-1-{(phenyl-sulphanyl)methyl]propyl}amin 0)-3-nitrobenzenesulphonamid €,

N-{[(4aS,R)-3-([1,1 -biphenyl]-2-ylmethyl)-2,3 ,4,4a,5,6-hexahydro-1 H-pyrazino-[1,2- aJquinolin-7-yljcarbonyl}-4-({(1 R)-3-(dimethylamino)-1- [(phenylsulfanyl)- Yo methyl]propyl}amino)-3-nitrobenzenesu Iphonamide,

- 1” -

N-{[2-([1,1-biphenyl]-2-ylmethyl)-1,2,3 ;4-tetrahydropyrazino[ 1,2-a]indol-8-yl]-carbonyl} -4-({ (1R)-3-(dimethylamino)-1- [(phenylsulphanyl)methyl]propyl}-am ino)-3- nitrobenzenesulphonamide,

N-{[2-([1,1'-biphenyl]-2-ylmethyl)-1 »2,3,4-tetrahydropyrazino[1,2-a]indol-8-yl]-carbonyl}-4-( {(1R)-3-(dimethylamino)-1-[(phenylsulphany)m ethyl]propyl}-amino)-3- 8 nitrobenzenesulphonamide bis(hydrochloride),

N-({2-[(4'-chloro-[1,1'-biphenyl]-2 -yDmethyl]-1,2,3 »4-tetrahydropyrazino[1,2-a]-indol-8- yl} carbonyl)-4-({(1R)-3-(dimethylamino)-1-[(phenylsulphanyl)methyl] -propyl}amino)- 3-nitrobenzenesulphonamide,

N-({2-[(4'-chloro-[1,1 "-biphenyl]-2-yl)methyl]-1,2,3 ,4-tetrahydropyrazino [1,2-a]-indol- Ve 8 -yl}carbonyl)-4-({(1R)-3-(dimethylamino)-1-[(phenylsulphanyl)methyl]- propyl}amino)-3-nitrobenzenesulphonamide bis(hydrochloride),

N-({(10aS,R)-2-[(4"-chloro-[1,1'-biphenyl] -2-yl)methyl}-1,2,3,4,10,10a-hexahydro-pyrazino [1,2-a]indol-8-yl} carbonyl)-4 -({(1R)-3-(dimethylamino)-1- [(phenyl-sulphanyl)methyl]propyl}amino)-3-nitrobenzenesulphonamide, Yo

N-({(4aR)-3-[(4'-chloro-[1,1'-b iphenyl]-2-yl)methyl]-2,3,4,4a,5,6-hexahydro-1H- pyrazino[1,2-a]quinolin-8-yl} carbonyl)-4-( {(1R)-3-(dimethylamino)-1-[(phenyl-sulphanyl)methyl]propyl}amino)-3-n itrobzenesulphonamide ,

N-({(4aR)-3-[(4'-chloro-[1,1 -biphenyl]-2-yl)methyl]-2,3,4,4a,5,6-hexahydro-1H-pyrazino[ 1,2-a]quinolin-8-yl} carbonyl)-4-({(1R)-3-(dimethylamino)-1-[(phenyl- Ye sulphanylymethyl]propyl} amino)-3-nitrobenzenesu Iphonamide bis( hydrochloride), yay

1m —

N-({(4aS)-3-[(4'-chloro-[1,1"-biphenyl}-2-yl)methyl]-2,3,4.4a,5 ,6-hexahydro-1H-pyrazino[ 1,2-a]quinolin-8-yl} carbonyl)-4-({(1R)-3 -(dimethylamino)-1-{(phenyl-sulphanyl)methyl]propyl}amino)-3-nitrobenzenesulphonamide,

N-({(4aS)-3-[(4'-chloro-[1,1'-biphenyl]-2-yl)methyl]-2,3,4,4a,5,6-hexahydro-1H-pyrazino [1,2-a]quinolin-8-yl} carbonyl)-4-({(1R)-3-(d imethylamino)-1-[(phenyl-© sulphanyl)methyl]propyl} amino)-3-nitrobenzenesulphonamide bis(hydrochloride),

N-{[(4aS)-3-([1,1"-biphenyl]-2-ylmethyl)-2,3 ,4,4a,5,6-hexahydro-1H-pyrazino[1,2-aJquinolin- 8-yl]carbonyl}-4-({(1R)-3-(dimethylamino)-1- [(phenylsulphanyl)- methyl]propyl}amino)-3-nitrobenzenesulphonamide,

N-{[(4aS)-3-([1,1'-biphenyl]-2-ylmethyl)-2,3,4,4a,5,6-hexahydro-1 H-pyrazino[1,2- Ve aJquinolin -8-yl]carbonyl}-4-({(1R)-3-(dimethylamino)-1-[(phenylsulphanyl)- methyl]propyl} amino)-3-nitrobenzenesulphonamide bi s(hydrochloride),

N-{[(4aR)-3-([1,1"-biphenyl}-2-ylmethyl)-2,3 -4,4a,5,6-hexahydro-1H-pyrazino-[1,2-aJquinolin- 8-yl]carbonyl}-4-({(1R)-3-(dimethylamino)-1-[(phenylsulphanyl)- methyl]propyl}amino)-3-nitrobenzenesulphonamide, Yo

N-{[(4aR)-3-([1,1"-biphenyl]-2-ylmethyl)-2,3,4,4a,5, 6-hexahydro-1H-pyrazino-[1,2-a] quinolin-8-yljcarbonyl}-4-({(1R)-3-(dim ethylamino)-1-[(phenylsulphanyl)- methyl]propyl}amino)-3-nitrobenzenesulphonamide tris(hydrochloride),

N-{[(4aS,R)-3-([1,1'-biphenyl]-2-ylsu Iphonyl)-2,3,4,4a,5,6-hexahydro-1 H-pyrazino[1,2] - ajquinolin-8-yljcarbonyl}-3-nitro-4-{ [2-(phenylsulphanyl)ethyl]- Ye amino} benzenesulphonamide,

- 1 —

N-({(4aS,R)-3-[(4'-chloro-[1,1'-biphenyl]-2-yl)methyl]-2,3,4,4a,5,6-hexahydro-1H - pyrazino[1,2-ajquinolin-8-yl} carbonyl)-4-{(1R)-3-(dimethylamino)-1- [(phenyl-sulphanyl)methyl]propyl}-3,4-dihydro-2H- 1,2,4-benzothiadiazine-7-sulphonamide 1,1- dioxide,

N-({(4aS,R)-3-[(4'-chloro-[1,1'-biphenyl]-2-yl)methyl]-2,3,4,4a,5 ,6-hexahydro-1H - 8 pyrazino[1,2-a]quinolin-8-yl} carbonyl)-4- {(1R)-3-(dimethylamino)-1- [(phenyl-sulphanyl)methyl]propyl}-4H-1,2 ,4-benzothiadiazine-7-sulphonamide 1,1-dioxide,

N-({(10a[alpha])-2-{(4"-chloro-[1,1'-biphenyl]-2-yl)methyl]-1,2,3,4,10,10a-hexa- hydropyrazino[1,2-a]indol-8-yl} carbonyl)-4-({(1R)-3-(d imethylamino)-1- [(phenylsulphanyl)methyl]propyl} amino)-3-nitrobenzenesulphonamide ,

N-({(10a[beta])-2-[(4"-chloro-[1,1"-biphenyl]-2-yl)methyl]-1,2,3,4,10,10a- hexahydropyrazino[ 1,2-a]indol-8-yl} carbonyl)-4-( {(1R)-3 -(dimethylamino)-1- [(phenylsulphanyl)methyl]propyl}amino)-3-nitrobenzenesu Iphonamide bishydrochloride, Yo

N-({(10a[alpha])-2-[(4"-chloro-[1,1"-biphenyl]-2-yl)methyl]-1,2,3,4,10,10a-hexa- hydropyrazino[1,2-a}indol-8-yl} carbonyl)-4-({(1R)-3-(4 -morpholinyl)-1-[(phenyl-sulphanyl)methyl]propyl} amino)-3- nitrobenzenesulphonamide bishydrochloride,

N-({(10a[alpha])-2-[(4'-chloro-[1,1"-biphenyl]-2-yl)methyl]-1,2,3,4,10,10a- hexahydropyrazino[ 1,2-aindol-8-yl} carbonyl)-4-({(1R)-3 -(4-morpholinyl)-1- Ye [(phenylsulphanyl)methyl]propyl}amino)-3-[(trifluoromethyl )sulphonyl [benzene]

- Vo — sulphonamide bihydrochloride,

N-[((4aR)-3-{[2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohexen-1-yl]methyl }-2,3,4,4a,5,6- hexahydro -1H-pyrazino[1,2-a]quinolin-8-yl)carbonyl]-4-({(1R)-3 ~-(4-morpholinyl)-1- [(phenylsulphanyl)methyl]propyl} amino)- 3-[(trifluoromethyl)- sulphonyl]benzenesulphonamide bishydrochloride, 8

N-[((10a[beta])-2-{[2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohexen-1-yljmethyl }- 1,2,3,4,10,10a- hexahydropyrazino [1,2-a] indol-8-yl)carbonyl]-4-({(1R)-3-(4- morpholinyl)-1-[(phenylsulphanyl)methyl]propyl}amino)-3- [(( trifluoromethyl)-sulphonyl]benzenesulphonamide bihydrochloride,

N-[((4aR)-3-{[4-(4-chlorophenyl)-3-pyridyl]methyl}-2,3,4,4a,5, 6-hexahydro-1H- yo pyrazino[1,2- a]quinolin-8-yl)carbonyl]-4-({(1 R)-2-(dimethylamino)-1- [(phenylsulphanyl)methyl]ethyl }amino)-3 -nitrobenzenesulphonamide trihydrochloride,

N-({(4aR)-3-[(4-amino-4'-chloro-[1,1 -biphenyl]-2-yl)methyl]-2,3,4,4a,5,6-hexahydro- 1H-pyrazino[1,2-aJquinolin-8-yl} carbonyl)-4-({(1R)-3-(dim ethylamino)-1- [(phenylsulphanyl)methy!]propyl}amino)-3 -nitro- benzenesulphonamide V trihydrochloride,

N-[((4aR)-3-{[4-(aminomethyl)-4'-chloro-[1,1"-biphenyl}-2-yljmethyl}-2,3,4,4a,5,6- hexahydro -1H-pyrazino[1,2-a]quinolin-8-yl)carbonyl]-4-( {(1R)-3-(dimethylamino)-1- [(phenylsulphanyl)methyl]propyl} amino)-3 -nitrobenzene -sulphonamide trihydrochloride, Ye

N-[((4aR)-3-{[3'"-fluoro-4'-chloro-[1,1'-biphenyl]-2 -yllmethyl}-2,3,4,4a,5,6-hexahydro -

- 11 -

IH-pyrazino[1,2-a]quinolin-8-yl)carbonyl}-4-({(1R)-3-(dimethylamino)-1-[(phenyl sulphanyl)methyl]propyl} amino)-3-nitrobenzene -sulphonamide bihydrochloride,

N-[((4aR)-3-{[4'-(trifluoromethyl)-[1,1'-biphenyl]-2-yl]methyl}-2,3,4,4a,5,6-hexahydro- 1H -pyrazino [1,2-a]quinolin-8-yl)carbonyl]-4-({(1R)-3-(dimethylamino)-1- [(phenylsulphanyl)methyl]propyl} amino)-3-nitro-benzenesulphonamide 2 bishydrochloride,

N-[((4aR)-3-{[4'-cyano-[1,1'-biphenyl]-2-yllmethyl}-2,3,4,4a,5,6-hexahydro-1H-pyrazino[1] ,2-a]quinolin-8-yl)carbonyl]-4-({(1R)-3-(dimethylamino)-1- [(phenylsulphanyl)methyl]propyl}amino)-3-nitrobenzenesulphonamide bishydrochloride,

N-({(4aR)-3-[2-(1,3-benzodioxol-5-yl)benzyl]-2,3,4,4a,5,6-hexahydro-1H-pyrazino[ 1,2- a ]quinolin-8-yl}carbonyl)-4-({(1R)-3-(dimethylamino)-1- [(phenylsulphanyl)methyl]propyl} amino)-3-nitrobenzenesulphonamide bishydrochloride,

N-({(4aR)-3-[(4'-chloro-[1,1'-biphenyl}-2-yl)methyl]-2,3,4,4a,5 ,6-hexahydro-1H- Yo pyrazino[1,2-a}quinolin-8-yl} carbonyl)-4-({(1R)-3-(4-morpholinyl)-1- [(phenylsulphanyl)methyl]propyl}amino)-3-nitrobenzenesulphonamide bihydrochloride ,

N-({(4aR)-3-[(4"-chloro-[1,1"-biphenyl]-2-yl)methyl]-2,3,4,4a,5,6-hexahydro-1H-pyrazino [1,2-a]quinolin-8-yl} carbonyl)-4-({(1R)-3-(4-morpholinyl)-1- Ye. [(phenylsulphanyl)methyl]propyl} amino)-3-[ (trifluoromethyl)sulphonyl]-

Yay

- 11 - benzenesulphonamide bihydrochloride,

N-({(4aR)-3-[(4'-chloro-[1,1'-biphenyl]-2-yl)methy!]-2,3,4,4a,5,6-hexahydro-1H- pyrazino[1,2-a]quinolin-8-yl} carbonyl)-4-({(1R)-3-(4-methyl-1-piperazinyl)-1 H- [(phenylsulphanyl)methyl]propyl} amino) -3-nitrobenzenesulphonamide bishydrochloride, ©

N-({(4aR)-3-[(4'-chloro-[1,1"-biphenyl]-2-yl)methyl]-2,3,4,4a,5,6-hexahydro-1H-pyrazino [1,2-a]quinolin-8-yl} carbonyl)-4-( {(1R)-3-(1-piperidyl)-1- [(phenylsulphanyl)methyl]propyl} amino)-3-nitrobenzenesulphonamide bishydrochloride,

N-({(4aR)-3-[(4'-chloro-[1,1"-biphenyl]-2-yh)methyl]-2,3,4,4a,5,6-hexahydro-1H- Vo pyraz ino[1,2-aJquinolin-8-yl} carbonyl)-4-({(1R)-3-(1-pyrrolidinyl)-1- [(phenylsulphanyl)methyl]propyl} amino)-3-nitrobenzenesulphonamide bishydrochloride,

N-({(4aR)-3-[(4"-chloro-[1,1"-biphenyl]-2-yl)methyl]-2,3,4,4a,5,6-hexahydro-1H-pyrazino [1,2-a]quinolin-8-yl} carbonyl)-4-({(1R)-3-(3,6-dihydro-1(2H)-pyridyl-1- Vo [(phenylsulphanyl)methyl]propy !} amino)-3-nitrobenzenesulphonamide bishydrochloride,

N-({(4aR)-3-[(4'-chloro-[1,1"-biphenyl]-2-yl)m ethyl]-2,3,4,4a,5,6-hexahydro-1H- pyrazino[1,2-a]quinolin-8-yl}carbonyl)-4-({(1R)-3-(1-azepanyl)-1-[(phenyl- Ye sulphanyl)methyl]propyl} amino)-3 -nitrobenzenesulphonamide bihydrochloride,

—_1 A_

N-({(4aR)-3-[(4'-chloro-[1,1'-biphenyl]-2-yl)methyl]-2,3,4,4a,5,6-hexahydro-1H-pyrazino [1,2-a]quinolin-8-yl} carbonyl)-4-({(1R)-3--((1R,5S)-3-azabicyclo-[3.1.0]hex-3-yl)- 1-[(phenylsulphanyl)methyl]propyl} amino)-3-nitrobenzene-sulphonamide bishydrochloride, sodium N-({(4aR)-3-[(4'-chloro-[1,1"-biphenyl]-2-yl )methyl}-2,3,4,4a,5,6-hexahydro- 5 111-0212100] 1,2-a]quinolin-8-yl} carbonyl)-4-({(1R)-3-(dimethylamino) )-1-[(phenyl- sulphanyl)methyl]propyl}amino)-3-nitrobenzenesulphonamide with an acceptable acid Lede and addition salts ¢ diastereoisomers the coenomers and pharmaceutically acceptable bases or pharmaceutically acceptable bases of the preferred compounds of the invention are a part elie of the invention Vo.. The invention Usa relates to a process for preparing a compound of formula (I) characterized by that a compound of formula (11) is used as a starting material: (IID)

NN

Cy Cl where 7 is as defined for the formula (I) and “©” is a compact three-ring system of formula (avy 0

1 89 — - av) . A N Iw ) ( TN 1 Rs > where ony X 5 eA and “; 5 RY is as defined with respect to formula (1); the group is 7-01- Connected at position or 5 of the three-ring system call, where the compound of formula (111) is condensed in a basic medium in the presence or absence of a conjugation factor © with a compound of formula: (V) (V) Cl ry H>N ~ so; 2X b where SRY is defined with respect to the formula (I) for a compound of formula (VD): (VD) Cl R y Y +0 2X Ry y 7

- and - where R*5¢Y 5 “Cy is as defined by (JB) which is condensed with a compound of formula HNR7RY where Ry and 87 are as defined with respect to formula (1) to obtain compound of formula (1/8); a special case of compound of formula 0 (Ia) J 0 Cy NH | 2 SO, 2X ~ and b + > with o where Cy Walaa 5 RY 5 Ry RY shall be as defined before; which may be purified according to a conventional separation technique; and which, if desired, is converted to salts by addition of Gay acid or Gay acid base sll ¢ Gay can optionally be separated into J of its isomers Si, for a conventional separation technique. Expertise in this field by way of conventional chemical reactions illustrated previously published in this field A useful aspect relates to a process for the preparation of a compound of formula (1), characterized by the fact that a compound of formula (IIT) is used as a starting material: 111%( IN Cy OH \o Y14Y

Y 1 - — where 7 as defined for the formula (1) 5 ii Cy is a combined three-ring system of formula (IV) b (Iv) A N Loa ( ) a 1 Ry > where ny (RP 5 XA and “ is as defined with respect to formula (1) and the group –Y-OH© is attached at position 8 or 5 of the free tricyclic system: the compound is condensed which has formula (111); in a basic medium in the presence of a coupling agent; with a compound of formula (VII) (VID) Rs or HoN 2 so; 29 2 where Re 5 Rs (Ry) shall be as defined before with respect to formula (1) Vo in order to obtain a compound of formula (1); which can be purified according to a conventional separation technique; and which, if desired, is converted into added salts thereof using a pharmaceutically acceptable acid or a pharmaceutically acceptable base, which can optionally be separated into its isomers Gy of the 57T separation technique

- YY - traditional. Compounds with formulas (111) and (711) are either commercial compounds or can be accessed by an experienced person in this field through conventional chemical reactions described in what has been previously published in this field.

© The pharmacological study of the compounds of the invention showed that they have pro-apoptotic properties. The ability to reactivate the process of cell death in cancer cells is of great therapeutic importance in the field of cancer treatment. more specifically; The Gay compounds of the invention will be useful in the treatment of cancers that are resistant to chemotherapy or radiation therapy; In cases of malignant haemopathies,

0 and in small cell lung cancer. Among the types of cancer treatment, cancers that can be taken into consideration; It can be mentioned - for example, but not limited to - cancers of the bladder; brain; and the breast; and the uterus; chronic lymphoid leukemias and cancers of the colon and esophagus; And liver liver ¢ and lymphoblastic leukemias diseases «

1 follicular lymphomas; melanomas, malignant haemopathies, and myelomas; ovarian cancers, non-small-cell lung cancers, prostate cancers, and small-cell lung cancers.

( ) Also, the present invention relates to pharmaceutical compositions that include at least one compound of formula 0

seemed

— Y Y —

Alone or in combination with one or more pharmaceutically acceptable excipients.

Among the pharmaceutical compositions according to the invention, those compositions may be mentioned more specifically

suitable for oral ¢ or nasal administration; or under or through the skin (per-or).

transcutaneous « or rectal ¢ or perlingual » or ocular administration or respiratory administration ¢ especially

Tablets 5 + rivets, dragees + and sublingual tablets

tablets ¢ and sachets; and packages; gelatin capsules; And tablets placed

carving the tongue glossettes; lozenges »; suppositories ¢ suppositories and creams; ointments;

gels for use on the skin; ALE drinkable or injectable ampoules 0 .

The dose varies iy for gender and age; patient weight; method of administration; the nature of the therapeutic effect; or

any of the concomitant treatments; It ranges from 10010 mg to 1 g per YE hour in tye given.

one or more.

moreover; The present invention Wal relates to a combination of a compound of formula (1) with an antiagent

Yo for cancer selected from: genotoxic agents; mitosis-related toxins; and factors

anti-metabolites; protease inhibitors; and kinase inhibitors » and using this

The type of combination in the manufacture of drugs for use in the treatment of cancer.

The compounds of the invention may also be used in combination with radiotherapy for the treatment of

A Y — this and the following preparation methods and examples illustrate the invention; But it does not reduce it in any way. Method of preparation) 2 ‎(4aS,R)-3-[(4'-Chloro-1,1'-biphenyl]-2-yl)methyl}-2,3,4,4a,5,6-hexahydro-1H - pyrazinof1,2-a]quinoline8-carboxylic acid hydrochloride 2 Hazardous A: 6-Methoxy-2-quinolinecarbaldehyde Selenium oxide was added in quantities to a solution of (£Y) 6-methoxy-2-methylquinoline g) in 40,600 mL of a mixture of [dioxane 11:0 (© 7); The mixture as a whole was then heated at reflux overnight. after that; the mixture was left to cool; Then the metal was removed by filtration and 0 concentration was carried out for drying. The resulting dark brown solid was purified by chromatography on a (01 / Av AcOEt / heptane) silica column. The title product was obtained in the form of a white solid in step B: 2-{[(6-Methoxy-2-quinolyl (methyl]Jamino} ethanol 4.0 mL of 3-aminopropanol was added to a suspension of the compound obtained in step 0 A (an YA) in 100 mL of EtOH and the mixture was returned all using a Dean-Stark apparatus overnight.Then, the reaction mixture was concentrated for drying and 100 mL of EtOH was withdrawn at zero temperature, then 0 g of NaBH was added, in quantities Then, the whole mixture was heated at reflux overnight, and the reaction mixture was concentrated

Yo - - for drying; Hydrolyzed at 0:11 and extracted with CHCl. Drying on MgSO and concentration for drying yielded an oil that gradually crystallized. Then, the crystals were crushed in diisopropyl ether, filtered and dried to obtain the title product in the form of crystals. Beige.© Step C: 2-{[(6-Methoxy-1,2,3,4-tetrahydro-2-quinolyl)methylJamino} ethanol

169 g lay Raney nickel was added to a solution of the compound obtained in step b (VF g) in a mixture of 0 / 5 0 © of 1 M KOH / MeOH (0111). Then, the whole mixture was stirred at ambient temperature overnight. Then the metal was removed by filtration and the filtrate was concentrated for drying. Then the residue was withdrawn in “CHCl”, and analyzed

1 0 with H,O and then extracted le times with .CH,Cl, after that ' and then collect the extraction products; dried at 0.24850; filtered and concentrated for drying. The resulting crystals were crushed in diisopropyl ether and filtered; and dried to obtain the title compound in the form of white crystals. Step D: (4aS,R)-8-Methoxy-2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-ajquinoline]

01 (g) to a suspension of compound obtained in step c (7.0 VA), 05 mM You at JSS temperature was added thereafter; The mixture of Lo-xylene (ml of 00 g) was heated overnight. The mixture was left to cool; Concentrate to dry and then slowly titrate hydrolyse without heating with stirring the entire mixture at © NaOH and adding (HO) using ambient temperature for 0 min. After that; the reaction mixture was extracted several times using

CHCl, 0 and drying it on (MgSO), and its concentration for drying to obtain a brown oil corresponding to the yield of

Y 1 - — heading” as it was used directly without refinement in the next step. Step E: (4aS,R)-3-Benzyl-8-methoxy-2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-a] -quinoline The compound that was dissolved Obtained in step D (lagm) in 100 ml of DMF, then 8 g of AAC, 6200 and 5.7 ml of benzyl bromide and 1100 mg of “Nal” were successively added and the mixture was heated as a whole at a mouth temperature m for a period of 1 hour.The concentration process was carried out by drying and withdrawing the remaining substance in LACOEt after “dl”, then washing the organic phase using “H,O”, then using a saturated LiCl solution, then using a NaCl solution Saturated The organic phase was dried on MgS 0 ¢ and concentrated for drying Calg Residual 3 purified by chromatography on an AcOEt/heptane (silica 0 40 / 0) column to obtain the title product as a colored solid Step F: (4aS,R)-3-Benzyl-2,3,4,4a,5,6-hexahydro-1H-pyrazino[ 1,2-a]quinolin-8-yl trifluoromethanesulphonate Yo A solution of 1 M CHCl, / BBr; was added to a solution of the compound obtained in step A (2 g) in 0 mL of CHCl at a temperature of zero 'a and then Stir the mixture as a whole, gradually returning to ambient temperature. after that; The temperature was maintained with stirring throughout the night. Then the mixture was returned to 0°C and 0©mL of MeOH was slowly added and the mixture was stirred at ambient temperature for 0min. after that; The reaction mixture was concentrated

Bae was dried and eluted several times with diisopropyl ether and the resulting beige crystals were filtered and dried. Then the crystals were dissolved in 100 ml of Wa11:0©” and 6111 ml of 5017 and the donor triflate (4 8.8 g) was added dropwise; And stir the mixture as a whole at ambient temperature. Hydrolysis was carried out using 0:11, followed by two extractions using WA:0:11. © organic extracts collected; Dry it at 14/850 and concentrate it for drying. after that; The residue was purified by column chromatography (1 / 4 AcOEt / heptane) silica to obtain the title product in the form of creamy white crystals. Step g: Methyl (4aS,R)-3-benzyl-2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-a]-quinoline-8-carboxylate was done. The compound obtained in step f (3 g) was dissolved in 0 ml of a mixture of (Y/Y) MeOH/DMSO and then 7.6 ml of BUN and 19 g of PA(OAC) were respectively added. ), and 0.175 g of the bonding compound (dppf), the mixture was degassed in an atmosphere of 00 for 01 minutes; then carbon monoxide was introduced in the form of bubbles for a period of (dad) Vr and it was - after That - made the mixture saturated with carbon monoxide for 115 minutes. LEY; The mixture was sealed as a whole (mile to enter the shed) and heated at a temperature of 65 C for ? hours. Then, allow the mixture to cool and remove the carbon monoxide using 0. after that; The reaction mixture was hydrolyzed with 11:0 and extracted with ACOEL 0. The organic extracts were collected; And dried at ,14850 and concentrated for drying. 01 The residue was then purified by silica column chromatography to obtain a yield

YA — — heading in oil form -crystallises Slay step z Methyl (4aS,R)-2,3,4,4a,5,6-hexahydro-1H-pyrazino[1 ,2-a] quinoline-8-carboxylate 00 714 g of C [PA 700 and then 7.4 g of NHCOOH were successively added to solution 2 of compound a obtained in step J (9 g) in Yoo mL of a mixture of 0 / Si (MeOH / THF) m ' as the whole mixture was heated at 0 8 C for 2 hours. Then + the reaction mixture was cooled and filtered; the filtrate was concentrated for drying 0 The resulting substance in “diisopropyl ether” was drawn, crushed and filtered, and concentrated for drying to obtain the title product as a white solid. 0 Step i: Methyl (4aS,R)-3-[(4'-chloro-[) 1,1 -biphenyl]-2-yl)methyl]-2,3,4,4a,5,6-hexahydro-1H- pyrazinof1,2-a]quinoline-8-carboxylate The compound that was dissolved Obtained in step H (V) g) in 0 ml of “DMF” and then Cad sequentially adding a mg of 0 mm KCl and z ml of: 4-chloro-2'-(chloromethyl) -1,1'-biphenyl Yo; and 1100 mg of “Nal” and the whole mixture was heated at 00°C for ¥ an hour. Then a concentration was performed for drying and the residue was withdrawn in ACOEt and washed with H,0 and a saturated solution of LiCl and then with a saturated solution of 120. The organic phase was dried over MgSO, and concentrated for drying. After (sla) the residue was purified

Y q —_ — ih uly Column chromatography of ACOEL / heptane (silica 90 / 0) to obtain the heading product as a creamy white solid. Step j: (4aS,R)-3- [(4'-Chloro-[1,1 -biphenyl]-2-yl)methyl]-2,3,4,4a,5, 6-hexahydro-1H- pyrazino[1,2-a]quinoline- 8-carboxylic acid hydrochloride 5 9 mL of 1 N HCL was added to a solution of 0.2 g of the compound obtained in step i in 4 mL of dioxane.Then the whole mixture was heated At the reflux temperature for a period of hours, then a concentration process was carried out for drying The resulting substance was crushed in diisopropyl cether and filtered and dried to obtain the title compound in Spa a solid of 01 white to bluish color Method of preparation? : (4aS,R)-3-[(4'-Chloro-[1,1 -biphenyl]-3-yl)methyl]-2,3 »4,4a,5,6-hexahydro-1H- pyrazino[1,2-a]quinoline-8-carboxylic acid The procedure used for the preparation method (0) was used with the substitution of: 4-chloro-2'-(chloromethyl)-1, 1 “biphenyl Yo) in step i by: 4-chloro-3'-(chloromethyl)-1,1'-biphenyl How to prepare?:

- and (4aS,R)-3-[(4'-Chloro-[1,1'-biphenyl]-4-yhmethyl]-2,3,4,4a,5,6-hexahydro-1 H- pyrazino[1,2-a]quinoline-8-carboxylic acid hydrochloride was used for user procedure for preparation method 1 + with substitution: 4-chloro-2'-(chloromethyl)-1,1'-biphenyl in Step I by 4-chloro-4'-(chloromethyl)-1,1'- biphenyl 5 Preparation method 2 (4aS,R)-3-([1,1'-Biphenyl]-2-ylmethyl)- 2,3,4,4a,5,6-hexahydro-1 H-pyrazino[1,2-a]quinoline-8-carboxylic acid hydrochloride then use | for user action for method 1 + with substitution: ' 4-chloro-2'-(chloromethyl)-1,1'-biphenyl in Step I by 2-(chloromethytl)-1,1'-biphenyl Ve Preparation method ie (4aS,R)-3- (2-Benzylbenzyl)-2,3,4,4a,5,6-hexahydro- 1 H-pyrazino[1,2-a]quinoline-8- carboxylic acid hydrochloride and then using the procedure used for the preparation method 1 ; with the replacement of : 4-chloro-2'-(chloromethyl)-1,1'-biphenyl Vo by 1-benzyl-2-(chloromethyl)benzene

y Vy — method of preparation A (4aS,R)-3-[2-(2-Phenylethyl)benzyl]-2,3,4,4a,5,6-hexahydro-1H-pyrazino[ 1 ,2- aJquinoline-8-carboxylic acid hydrochloride and then using the procedure used for preparation method 1; With the substitution of : 4-chloro-2'-(chloromethyl)-1,1'-biphenyl ~~ © in step 1 by the : 1-(chloromethyl)-2-(2-phenylethyl)benzene method Preparation BY (4aS,R)-3-[(4'-Chloro-[1,1'-biphenyl]-2-yl)methyl]-2,3,4,4a,5,6-hexahydro- 1H- pyrazino[ 1,2-a]quinoline-7-carboxylic acid hydrochloride 01 then using } for user procedure of preparation method 1 + substituting: 6-methoxy-2-methylquinoline in step f By .5-methoxy-2-methylquinoline Preparation tA (4aS,R)-3-([1,1'-Biphenyl]-2-ylmethyl)-2,3,4,4a, 5,6-hexahydro-1H-pyrazino[ 1,2- a]quinoline-7-carboxylic acid hydrochloride Yo Then |« Usage | To make a touch to a user of preparation method 1; With the : 6-methoxy-2-methylquinoline replaced in Step A by :

— Y Y — 5-methoxy-2-methylquinoline, and replacing 4-chloro-2'-(chloromethyl)-1,1'-biphenyl in step i by the -2-(chloromethyl)-1,1"-biphenyl method Preparation 3: 2-([1,1'-Biphenyl]}-2-ylmethyl)-1,2,3,4-tetrahydropyrazino[ 1,2-a]indole-8-carboxylic acid hydrochloride 2

Ethyl 5-methoxy-1H-indole-2-carboxylate A:3 slaall V£.0 mL of thionyl chloride was added dropwise using a distillation funnel to a suspension of 01 g of 5-methoxy-1H -indole-2-carboxylic acid in 100 ml of absolute ethanol at a temperature a ia then let the mixture gradually return to the ambient temperature once the 0 addition process is completed; Then gently heat it at return temperature for ; hours. after that; The reaction mixture was concentrated and the product was pulverized in diisopropyl ether and filtered; and dried. The title product was obtained as a dark brown solid.

Ethyl 1-(cyanomethyl)-5-methoxy-1H-indole-2-carboxylate Step B: Add 708 g of the compound obtained in Step A dissolved in 1560 mL 01 of anhydrous DMF Drop by using a distillation funnel a suspension of 507 g of NaH (10 7) in 0 mL of (ey DMF); the mixture was stirred for Ve min at ambient temperature; then VY mL was added of chloroacetonitrile and the whole mixture was stirred overnight at ambient temperature. Thereafter ¢ then the reaction mixture was concentrated for drying, withdrawn in cACOE, Gil analyzed with 10, then extracted with Cd ya using 01 hm. After that, then combined For the organic phases

— vy —

NaCl, then using a saturated solution of LiCl, washing them using a saturated solution of ' phases, filtering them, and concentrating them for drying. The solid was purified by MgSO, and dried to obtain the heading product in (0 / 90 AcOEt / heptane) silica gel chromatography. 2,3,4-tetrahydropyrazino[ 1,2-ajindole Step C: Drop molar THF in 1 commercial aluminum hydride ml of OV solution to which g of a solution of the compound was added. obtained in step B 17.75 using a funnel distilled to aqueous at zero temperature.Then the mixture was allowed to gradually return to THF ml from 1500 at

Vo at ambient temperature and gently heated at a temperature J for arg 2 for ? hours. after that ; Then the mixture was allowed to cool and returned to a temperature of 0 °C, and a hydrolysis was carried out using a saturated solution of Rochelle's salt, then the reaction mixture was extracted using AcOEt, and the organic extracts were collected, washed with a saturated solution of (NaCl) and dried on MgSO, and its concentration for drying, and then obtaining and gm of brown oil corresponding to the yield of the heading.

10 Step D:

2-([1,1'-Biphenyl]-2-ylmethyl)-8-methoxy-1,2,3,4-tetrahydropyrazino[ 1,2-a]indole of the compound made fe by 1 For user action of step 1 of prepare method J then use : get in step c and replace

SJ _ 4-chloro-2'-(chloromethyl)-1,1'-biphenyl by 2-(chloromethyl)-1,1'-biphenyl by : 2-(chloromethyl)-1,1'-biphenyl. . The title product was obtained in the form of a solid with step E: 1,2-a]indol-8-yl 8 |100 a tom ml Nabt4-160, 1,2,3 -(Int.6 2-7111[ 31080- 11.1 )-2, trifluoromethanesulphonate, then using (J) for the procedure used for the step and from the preparation method (A), and then obtaining the title product in the form of a yellow-orange solid. step f: . Methyl 2-([1,1'-biphenyl}-2-ylmethyl)-1,2,3,4-tetrahydropyrazino[ 1,2-a]-indole-8- Ye carboxylate was used. For step g of preparation method 1. The title product was obtained as a yellowish solid. Step g: : Yo then use J for the user action of step y of the preparation method ads A get the address output as a yellow solid sala . Bed

Yo - - Method of preparation HAR 2-[(4'-Chloro-[1,1'-biphenyl}-2-yl)methyl]-1,2,3,4-tetrahydro-pyrazino[ 1, 2-a}indole8- carboxylic acid hydrochloride The procedure used for preparation method 9 was used; With : 2-(chloromethyl)-1,1'-biphenyl 5 replaced in step d by : 4-chloro-2'-(chloromethyl)-1,1'-biphenyl . Preparation: 1 (10aS,R)-2-[(4'-Chloro-[1,1'-biphenyl]-2-yl)methyl}-1,2,3,4,10,10a- Hexahydropyrazino[1,2-a]indole-8-carboxylic acid hydrochloride 0 Step 1 Methyl 2-1(4'-chloro-[1,1'-biphenyl]-2-yl)methyl]- 1,2,3,4-tetrahydro-pyrazino[1,2-aJindole-8-carboxylate] The procedure used for the preparation of 9 steps a through f; With : 2-(chloromethyl)-1,1'-biphenyl replaced in step d by : 4-chloro-2'-(chloromethyl)-1,1-biphenyl 0 .

v4 — _ step b: Methyl (10aS,R)-2-[(4'-chloro-[1,1'-biphenyl]-2-yl)methyl]-1,2,3,4,10 ,10a-hexahydropyrazino[1,2-a]indole-8-carboxylate 0.1978 g of NaBH3CN at ambient temperature was added to a solution of 0.1 ©g of the compound that Obtained in step a in © ml of acetic acid . The reaction mixture was stirred for 8; hour. after that; The mixture was hydrolyzed with saturated NaHCO; Then it was extracted using AcOEt, the organic phases were combined, then washed with a saturated solution of (NaCl), dried at 21850, filtered, and evaporated for drying. After that, the title compound was purified by chromatography on silica gel. Step C: (10aS,R)-2-[(4'-Chloro-[1,1'-biphenyl]-2-yl)methyl]-1,2,3,4,10,10a- hexahydropyrazino [1,2-a]indole-8-carboxylic acid hydrochloride J was used for the procedure used for step j of preparation method Je) of the compound obtained in step b. \o Method of preparation HAR (4aS)-3-[(4'-Chloro-[1,1'-biphenyl]-2-yl)methyl]-2,3,4,4a,5,6 -hexahydro-1H- pyrazino| 1,2-a]quinoline-8-carboxylic acid hydrochloride

Step A: (4aS)-8-Methoxy-3-[(2S)-2-methoxy-2-phenylethanoyl}-2,3.4,4a,5,6-hexahydro- 1H-pyrazino[1,2] -a]quinoline at the beginning; 71.5 ml of thionyl chloride was added to a solution of 4.94 g of : S-methoxyphenylacetic acid ~~ © in 100 ml of CHyCly. The reaction mixture was heated at 501°C for half a cap Then it was allowed to cool to ambient temperature. An evaporation-drying process was carried out in order to obtain the oil. (Lil) The resulting oil in 171 ml of CH,Ch was added to a solution of 1 g of the compound then obtained in step d of preparation method 1 in 171 ml of CHCl and 6074 ml of 1 N NaOH.Then, the whole mixture was stirred vigorously at ambient temperature for 1 hour.The two phases were separated and an extraction was carried out once using CH,Ch., after washing with a saturated solution of NaCl and drying on MgSO, ¢ and then performing a concentration process for drying 0. The mixture was purified by chromatography and speckled on (Yo / 1 AcOEt / petroleum ether) silica to obtain a mixture of two diastereoisomers. Thereafter, the diastereoisomers |0 were separated by photopreparative liquid chromatography on Chiralpak AD using 1 as solvent and separating liquid.Step B: (4aS)-8-Methoxy-2,3,4 ,4a,5,6-hexahydro- 1H-pyrazino[1,2-a]quinoline 1.1 g of KOtBu was added to a solution of 151. ?g of the compound obtained in step i in 150 ml of THF and the reaction mixture was stirred at ambient temperature for Yay

YA - Half a day then all night. The THF was removed by evaporation, then the reaction mixture was hydrolyzed with 110 and extracted with 0011 M. After washing with a saturated solution of NaCl and then drying on MgSO, a concentration was carried out for drying. The mixture was purified by chromatography and flashed onto 0.* / © | 40) NH, OH | MeOH | CH,CL,) silica gel Obtaining the title product in © oil image. Step z (4aS)-3-[(4'-Chloro-[1,1'-biphenyl]-2-yl)methyl]-2,3,4,4a,5,6-hexahydro-1H- pyrazino[1,2-a]quinoline-8-carboxylic acid hydrochloride The procedure used for steps e through j of preparation method 1 was used starting with compound 01 which was then obtained in step b

Preparation: 1 (4aR)-3-[(4'-Chloro-{1,1'-biphenyl]-2-yl)methyl]-2,3,4,4a,5,6-hexahydro -1H- pyrazino[ 1 2-a]quinoline-8-carboxylic acid hydrochloride The procedure used for the NY preparation method in step a was used using the other isomer

Ade obtained 0

Method of preparation: (4aS)-3-([1,1'-Biphenyl]-2-ylmethyl)-2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-aJquinoline] -8-carboxylic acid hydrochloride

Y q —_ then use the procedure used for preparation method VY ; With the substitution of: 4-chloro-2'-(chloromethyl)-1,1'-biphenyl in step da of preparation method 1 by: 2-(chloromethyl)-1,1'-biphenyl . Preparation AN (4aR)-3-([1,1'-Biphenyl]-2-ylmethyl)-2,3,4,4a,5,6-hexahydro-1 H-pyrazino[1,2-] © aJquinoline-8-carboxylic acid hydrochloride Procedure used for preparation method VY with substitution: 4-chloro-2'-(chloromethyl)-1,1'-biphenyl in Step I of Preparation 1 by 2- (chloromethyl)- 1,1'-biphenyl 0 | Method of preparation NT (4aS,R)-3-([1,1'-Biphenyl]-2-ylsulphonyl)-2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2] - aJquinoline-8-carboxylic acid hydrochloride Step A: 3-([1,1'-Biphenyl]-2-ylsulphonyl)-8-methoxy-2,3,4,4a,5,6-hexahydro- 1 H-pyrazino[ 1,2-a]quinoline Vo The procedure used for step e of the preparation method) ¢ was used with benzyl bromide metabolization by [1,1'-biphenyl]-2-sulphonyl chloride. Yay

— and step b: 3-([1,1'-Biphenyl]-2-ylsulphonyl)-2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-a]quinoline- 8-carboxylic acid hydrochloride The procedure used for the steps and; Part j of preparation method 1 starting with the compound obtained in step a. Preparation NY 3-[(4'-Chloro-[1,1'-biphenyl]-2-yl)methyl]-1,2,3,4,4a,5,6,7-octahydropyrazino[1 ,2- a][1]benzazepine-9-carboxylic acid Step | : 6-Methoxy-3,4-dihydro-1(2H)-naphthalenone O-methyl-oxime 0 was added 18.97 g of 1182110041120 and 77.19 g of HCLLMEONH2 to a solution of 64 g of 6- methoxy-3,4-dihydro-1(2H)-naphthalenone in 9000 ml of methanol. after that; The reaction mixture was stirred at ambient temperature for 1 hour. after focus; The residue was withdrawn into a mixture of CH2CI2/1120 and the organic phase was washed with cele and dried on magnesium sulphate; and focus it to get the expected output. 0 Step B: N-(6-Methoxy-1,2,3,4-tetrahydro-naphthalen-1-y1)-O-methyl-hydroxylamine 177.7 mL of the complex of pyridine was added BH; to a solution of 10 g of the compound obtained in step i in 100 mL of ethanol . Once the reaction mixture is brought to a temperature of 0°C; 100 ml of 7.5 N 1101 solution was added dropwise, over the course of “hours”. The mixture was returned to ambient temperature and stirred for 1 hour; Then it's done

- 1 -

Addition of a saturated solution NaHCO; Then the organic phase was dried on magnesium sulphate and concentrated. and purified by silica column chromatography (ACOEL / heptane) to obtain the expected yield.

© Step C: 7-Methoxy-2-vinyl-2,3,4,5-tetrahydro-1H-1-benzazepine was added 145 mmol of bromovinyl magnesium in V0 ml of THF To a solution of 10 g of the preceding compound in 100 mL of THF the addition process was carried out at zero temperature over a period of 400 minutes; Then the reaction mixture was returned to ambient temperature. after stirring for 1 hour; The Uke mixture was analyzed using an ele drip at 0 °C;

organic phases and then extract the aqueous phase using and [011:0. The organic phases 0 were combined, filtered and concentrated. after that"; The residue “magnesium sulphate” was purified and dried to obtain the resulting (AOE / heptane) silica by predictive column chromatography. Step D: tert-Butyl 7-methoxy-2-vinyl- 2,3,4,5-tetrahydro-1H-1-benzazepine- 1-carboxylate Vo 0.97 g of compound 7.46 g of 300:0 3 1.00 g of 162:00 was added to a solution of M and stirred 61 The reaction mixture was heated to a temperature of THF step c in 10 ml h. after dilution in a mixture of 8.601/11:0; The aqueous phase was extracted using 01L and EL solution; It was washed using organic phases, then the organic phases were combined with “AcOEt

NaCl Ye is saturated; dried on magnesium sulphate; and its nomination; and its focus. after that; has been purified

gy — residue produced by column chromatography (AcOEt/heptane) silica to yield the expected yield. The hazardous ones are: Methyl 7-methoxy-2,3,4,5-tetrahydro-1H-1-benzazepine-2-carboxylate 11 ml of a 7.5 N NaOH solution in methanol was added to a solution of 1 g of © the above compound in 90 mL of A011:0. The whole mixture was cooled to a temperature of -VA m and ozone vapor was used. As soon as the distinctive blue color appeared, the reaction mixture was analyzed in an aqueous solution and extracted using 00151 M. The organic phases were combined, dried over magnesium sulphate, and filtered; and its focus. The residue was then dissolved in the HCI solution; standard in dioxane . after neutralization; The aqueous phase was extracted using 0 1:211 and the organic phases were combined; dried over magnesium sulphate and filtered; and its focus. after that; The resulting residue was purified by column chromatography (MeOH / CH,CL) silica to obtain the expected yield. Step F: Methyl 1-({[(benzyloxy)carbonylJamino}acetyl)-7-methoxy-2,3,4,5-tetrahydro-1H-1-benzazepine-2-carboxylate 1 was added. 7 g of PCs in quantities at zero temperature to a solution of VEY g of [(benzyloxy)-carbonylJaminoacetic acid in 0 ml of THF, then the whole mixture was stirred at the same temperature for 1 h. Thereafter, a solution of 01 g of step compound 0 oh ml of THE and + © ml of pyridine was added drop by drop at Bla safram to the 0 | reaction mixture over an hour.Then the mixture was brought to ambient temperature and stirred for 10 minutes

cm an hour. The resulting heterogeneous mixture was hydrolyzed drop by drop at Saphram temperature and then extracted using 80011. The organic phases were combined; and washed with a solution of NaHCO; saturated with a saturated solution of (NaCl), dried over magnesium sulphate, filtered, and concentrated. Then, the resulting residue was purified by chromatography on a (ACOE / heptane) silica© column to obtain Expected yield.Step g: 9-Methoxy-2,3,4a,5,6,7-hexahydropyrazino[1,2-a]{1]benzazepine-1,4-dione was added consecutively by ¥ g 5C [Pd V0 £1 g of NHCOOH to a solution of 10 g of the compound obtained in step and in £00 mL of a mixture of MeOH/THF (Y/Y) 0 then The whole mixture was heated at 00 C for 10 hours. after that; The reaction mixture was cooled; his candidacy; and concentrate for drying. The resulting substance in cdiisopropyl ether was drawn, crushed, filtered and concentrated for drying to obtain the expected compound. Step h: 3-Benzyl-9-methoxy-2,3,4a,5,6,7-hexahydropyrazino[ 1,2-a][ 1 Jbenzazepine-1,4-dione VO added V g of The compound obtained in step g in £00 mL of DMF at 0 °C drop by drop over an orbit of ? h to a heterogeneous solution of 06 g of NaH 0 in ¾ mL of DMF after returning to ambient temperature; has been added; ml of benzyl bromide over “0” minutes; then the reaction mixture was stirred for 1 hour VT. After concentration, the Yo residue was withdrawn at 0 °C into a mixture of 86011 and a saturated NaHCO solution. Then

The aqueous phase was extracted using 8001, then the organic phases 0288016 were combined and washed using a saturated 101 solution; dried on magnesium sulphate, filtered and concentrated. after that; The residue was purified by silica column chromatography (AcOEt/heptane) to obtain the expected compound. © Step i: 3-Benzyl-9-methoxy-1,2,3,4,4a,5,6,7-octahydropyrazino[ 1,2-a][ 1]-benzazepine added 7.71 g of ,110311 in quantities at 0 °C into a solution of 1 g of the compound obtained in step h in 150 mL of THF thereafter; The reaction mixture was stirred at the same temperature for Ye min. Then 1114 ml of the complex EO .11 0 pli drop was added at zero temperature over the course of 1 hour. After returning to ambient temperature; The reaction mixture was kept back for 10 hours; Addition of 0 mL of a standard HCI solution drop by drop at 0 °C. after that; The reaction mixture was heated at reflux for 1 hour before being hydrolyzed with 50 mL of standard NaOH© until a pH of © was reached. The aqueous phase was extracted using (AcOEt), then the organic phases (0) were combined, washed with a saturated NaHCO solution, dried on magnesium sulphate, filtered, and concentrated. After that, sald was purified. remaining by chromatography on (ACOEL / heptane) silica column to obtain the expected compound. Step j: 3-Benzyl-1,2,3,4,4a,5,6,7-octahydropyrazino[ 1,2-a][ 1Jbenzazepin-9-yl : p-trifluoromethanesulphonate The procedure used was For the step and method of preparation 1

g_Step k: Methyl 3-benzyl-1,2,3,4,4a,5,6,7-octahydropyrazino[ 1,2-a][ 1 Jbenzazepine-9-carboxylate The procedure used for step g was used Preparation method 1. Step for: Methyl 1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1] benzazepine-9-carboxylate © hydrochloride 700 mg of palladium catalyst was added to a solution of 1.0 g of the preceding compound in #8 ? mL of a solution of 1 N HCI in methanol. The resulting heterogeneous solution was then treated at 00 for £A hour at bar pressure. after that; The reaction mixture was filtered and rinsed 0 with methanol to yield the title compound as hydrochloride. step m: Methyl 3-[(4'-chloro-[1,1 "-biphenyl]-2-yl)methyl]-1,2,3,4,4a,5,6,7- octahydropyrazinof1, 2-a][1 Jbenzazepine-9-carboxylate | was used for user procedure for Lh step of preparation method 2 0 step n: 3-[(4'-Chloro-[1,1'-biphenyl]- 2-yl)methyl]-1,2,3 ,4,4a,5,6,7-octahydropyrazino[ 1,2-a][1]benzazepine-9-carboxylic acid

— 4 4 _— YAY mg of 11011 was then added to a solution of AO mg of compound step M in Yo mL of a mixture of (1 / £) 11:0 / dioxane thereafter; The mixture was stirred as a whole for a period of time; hours and concentrate for drying. after dilution in HCI 9.” Standard; The aqueous phase was extracted using 21. Next; The organic phases are merged; washed with NaHCO solution; © Saturated and saturated solution of “NaCl” dried on magnesium sulphate, filtered and concentrated. The resulting substance was hydrolysed in a mixture of HHO/ACN to obtain the title compound. Preparation YA (10a[alpha})-2-[(4'-Chloro-[1,1'-biphenyl]-2-yl)methyl}-1,2,3,4,10,10a- Hexahydropyrazino[ 1,2-a}indole-8-carboxylic acid ([alpha]=R or S) 0 The compound was obtained by separating the racemic mixture obtained in preparation method 11 on Chiralpak AD using diethylamine 5 « acetonitrile s » methanol as separation fluids. Retention time: ALY min. Preparation method 8: 6-(tert-Butoxycarbonyl)-3-[(4'-chloro-[1,1'-biphenyl]-2-yl)methyl]-2,3,4 ,4a,5,6- Vo hexahydro-1H-pyrazino[1,2-ajquinoxaline-8-carboxylic acid The compound was obtained by separating the racemic mixture obtained in the method

— 7 p. Prepare 11 on Chiralpak mL using diethylamine 5 « acetonitrile s » methanol as separation fluids. Retention time: 5.76 minutes Preparation method (Ye 6-(tert-Butoxycarbonyl)-3-[(4'-chloro-[1,1'-biphenyl]-2-yl)methyl]-2,3.4,4a ,5,6- ° hexahydro-1H-pyrazino[1,2-a]quinoxaline-8-carboxylic acid Step A: 4-[(Benzyloxy)carbonyl]-1-(2-nitrophenyl)-2- piperazinecarboxylic acid 14.0 ml of a solution of Y.0 NaOH N and then a solution of 7.07 g of : copper sulphate Ve in 50 ml of water was added to a solution of © g of : 2-piperazinecarboxylic acid dihydrochloride in 01 mL of water.The resulting blue solution was cooled to À©m, then 7.8 g of 118100 Spe 1 was added, followed by a solution of Y.AC mL of benzyl chloroformate in 01 mL of dioxane drop by drop After returning to the ambient temperature, the reaction mixture was stirred for 1 hour, then the head was removed by filtration to obtain: 4-[(benzyloxy)carbonyl]-2-piperazinecarboxylic acid chelated using Copper The last compound was dissolved in 7759 ml of water, then 0.000 g of EDTA was added and the reaction mixture was heated at a temperature of 680 C for 2 hours, then a concentration process was performed.

A — P — to dry. after that; The residue was withdrawn into VO mL of .DMSO, then 7.47 g of 2-fluoro-nitrobenzene 5 © 1 mL of EN was added and the reaction mixture was heated at 0°C for $A h . after returning to ambient temperature; The solution has been adjusted to reach the pH. using gle© HCI and then diluted in YOu ml of water; and extracted © using AcOEt. The organic phases were washed using cell and dried on magnesium sulphate; focus; and purified by chromatography on alumina (CHCl) silica (MeOH) to obtain the expected yield. Step b: Benzyl 5-0x0-1,2,4,4a,5,6-hexahydro-3H-pyrazino[ 1,2- a]quinoxaline-3-carboxylate Gd 01 add A g of iron powder in quantities to a solution of VY© g of compound step i in 100 mL of aceticacid The mixture was heated at m for 3 hours, then after returning to the ambient temperature, 0 5 ml of 1 N HCl was added, the solution was extracted using dichloromethane and the organic phases were combined, and dried on magnesium sulphate, then concentration.The residue was purified by chromatography on a (AcOEt/heptane) silica column 0 to obtain the expected yield.Step = Benzyl 8-bromo-5-o0x0-1,2,4,4a,5,6-hexahydro- 3H-pyrazino-[1,2-a]quinoxaline-3-carboxylate at °C and over ?min; a solution of 1.00 g of:

— ¢8 - N-bromosuccinimide in 71 mL of DMF to a solution of .4; g of compound of Step B in 0 mL of DMF the orange solution was stirred at the same temperature for 1.0 h; Then it was diluted in a mixture of 1:0 / 1 (AcOEt / \). The German phase was extracted using “AcOEt”, then the organic phases were combined and washed with water and then with a saturated solution of LiCl©. Before being dried on magnesium sulphate, filtered and concentrated, the resulting residue was purified by chromatography on a (AcOEt / heptane) silica column to obtain the expected yield. Step D: Benzyl 8-bromo-1,2,4,4a, 5,6-hexahydro-3H-pyrazino[1,2-a]quinoxaline-3-carboxylate 0 The procedure used for step da of method 117 was prepared using the compound obtained in the previous step. e: 3-Benzyl 6-tert-butyl 8-bromo-4a,5-dihydro-1H-pyrazino[1,2-a]-quinoxaline- 3,6(2H,4H)-dicarboxylate VO The procedure used for Step D of Preparation Method 117 was used using the compound obtained in the previous step. Step F:

0 _ m _ 3-Benzyl 6-tert-butyl 8-methyl 4a,5-dihydro-1H-pyrazino[1,2-a]-quinoxaline- 3,6,8(2H,4H)- tricarboxylate | The procedure used for step g of preparation method 1 using the compound obtained in the previous step was used. © Step G: 6-tert-Butyl 8-methyl 1,2,3,4,4a,5-hexahydro-6H-pyrazino[ 1,2-a]-quinoxaline-6,8- dicarboxylate Done Successively adding 177 g of VE2 GC [Pd ZV + mg of NHiCOOH to a solution of 101.0 g of the compound obtained in the step and in 50 mL of a mixture of THF/ (1 / 1) MeOH 0. The mixture as a whole was heated at 0.0 mm Sha for hours. After that, the reaction mixture was cooled, filtered, and concentrated for drying. Then the resulting material was withdrawn in diisopropyl cether. and crushed, filtered, and concentrated for drying to obtain the title compound.Step z 6-tert-Butyl 8-methyl 3-[(4'-chloro-[1,1"-biphenyl]-2-yl)methyl]-1 ,2,3.4,4a,5 -hexahydro- 6H-pyrazino[1,2-a]quinoxaline-6,8-dicarboxylate Vo The procedure used for step i of method 1 was prepared using the obtained compound In the previous step.Step i:

1 —_ g 6-(tert-Butoxycarbonyl)-3-[(4'-chloro-[1,1-biphenyl]-2-yl)methyl]-2,3,4,4a,5,6 - hexahydro-1H-pyrazino[1,2-a]quinoxaline-8-carboxylic acid The procedure used for step n of preparation method 117 was used using the compound obtained in the previous step.

2 Method of preparation: 71 6-(tert-Butoxycarbonyl)-3-[(4'-chloro-[1,1"-biphenyl]-2-yl)methyl]-5-0x0-2,3, 4,4a,5,6- hexahydro-1H-pyrazino[ 1,2-a]quinoxaline-8-carboxylic acid The compound given in the title was prepared by following the same steps as in the Yo method, but with two differences; They are: step d is omitted while in step e the Boc group is added

1117 (not DMF) in KoCOs and not JHNa in the presence of 0 1-Bromo-2-(bromomethyl)-4,4-dimethyl-1-cyclohexene : YY Method of preparation 4, 4-Dimethyl-cyclohexanone : | 3shall : In parts to a solution of PA/C 7 0 g of 1 ml of atoi 0 in (Je 0.1 mol” vor Ao was added ) 4,4-dimethyl-2-cyclohexen-1-one was hydrogenated and then stirred for two hours at ambient temperature under pressure of Yo by filtration and then concentrated to dryness. The resulting oil gradually crystallized. Then palladium was removed. The compound in the title was obtained as a white solid 2-Bromo-5,5-dimethyl-1-cyclohexene-1-carbaldehyde: Hazardous B

Ag (Yo.) YO ml of phosphorus tribromide was added dropwise to a mixture of 101 ml of 1:01© 5 18.7 ml of 0108. It was kept at Safram in an ice bath. Fully stirred at ambient temperature for 0 min. The reaction mixture (A Safram and *.10 aha) of compound A of step A dissolved in 900 mL of:011:01 was then cooled. All were stirred for ½ hours and gradually shifted to normal temperature before Poured onto a mixture of a solution of saturated NaHCO/IlG Then stirred for de La and extracted with ERO The organic phases were then collected Washed with a saturated NaCl solution; ads Drying on magnesium sulphate and then concentration to dryness The remaining amount was then vomited on a silica column (scale 0 heptane ACOEt 7 to 75 -(ACOEt 0) and the compound mentioned in the title was obtained. As colorless oil Step C: 2-Bromo-5,5-dimethyl-1-cyclohexen-1-yl)-methanol oa 7 of borohydride 0 was added in parts to a solution of 1 .48 grams of step B compound at 0’C in 171 mL of methanol. The mixture was completely stirred for 0 hours and gradually brought to normal temperature. The reaction mixture was then cooled to zero; then dissolved and extraction with D[011:01.] The organic phases ¢ were then collected and washed with saturated NaCl solution; It was dried over magnesium sulphate and finally concentrated to dryness. The compound mentioned in the title was obtained in the form of a colorless oil; Where it was purified using chromatography on a silica column (ACOEL / heptane). 0 Hazardous D 1-Bromo-2-(bromomethyl)-4,4-dimethyl-1-cyclohexene

oy — — FLAT 0 g of compound of Step C was dissolved in 10 mL of EO ¢ the entire mixture was kept at 0” M. 1 011 mL of phosphorus tribromide was then added dropwise Stirred at the mentioned temperature for 1 hour and 0 minutes. The reaction mixture was then rehydrated before extraction with EO. The organic phases were then collected; © was washed with a saturated NaHCO solution and then with a saturated NaCl solution; It was dried over magnesium sulphate and finally concentrated to dryness. The compound mentioned in the title was obtained in the form of a colorless oil, which was purified using a chromatogram on a silica ACOEL/heptane column ( ). How to prepare ?? : (4aR)-3-{[2-(4-Chlorophenyl)-5,5-dimethyl-1-cyclohexen-1-ylJmethyl}-2,3,4,4a,5,6- Ve hexahydro- 1H-pyrazino[1,2-a]quinoline-8-carboxylic acid hydrochloride Step A: Methyl (4aR)-2,3,4,4a,5,6-hexahydro-1H-pyrazino[ 1 ,2-a [quinoline-8-carboxylate] The procedure used is the same as that for steps a and b in the OY preparation with Ye the second stereoisomer selection. The resulting compound was subjected to the same treatments as those mentioned in steps h, e, g + h in preparation method A step b:

— mm - ‎Methyl (4aR)-3-[(2-bromo-5,5-dimethyl-1-cyclohexen-1-yl)methyl]-2,3,4.4a,5,6- hexahydro-1H -pyrazino[1,2-a]quinoline-8-carboxylate 3A » mL of aba + .) (EGN) of 0.11 5 Nal g of compound in preparation YY were added sequentially to A solution of 1776 grams of compound step A in 01 mL DMF © all was heated to pA for 2 hours.After cooling to normal temperature, the reaction mixture was analyzed and then extracted using: .001 M. The organic phases + were collected and washed with saturated LICH solution and then with saturated NaCl solution, then dried on magnesium sulphate and concentrated to dryness.The resulting material was then taken in diisopropyl cether was crushed and then filtered.The compound given in the title in was obtained as a substance

: a white solid that is pure enough to be used in the next step

iz step : Methyl (4aR)-3-{[2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohexen-1 -yl]methyl}- 2,3,4,4a, 5,6-hexahydro-1H-pyrazino[ 1,2-a] quinoline-8-carboxylate . 64 grams of PACly(Phs), then aba 0.1517 of Y.¢ 5 4-chlorophenylboronic acid ml of 05? Millar of aqueous solution and 8200 aqueous solution were added sequentially to a suspension of VEY g of compound step B in a mixture of EtOH [H20 [DME) (1° ml/ml tf ml). Everyone was degassed under argon atmosphere for 0 minutes, then cooled at 80°C for 11 hours. The reaction mixture was then filtered at ambient temperature. The filtrate was then dissolved and extracted using 0:11[2]. The organic phases were collected and Yo was washed with a saturated NaCl solution, then dried on magnesium sulphate and concentrated.

to dehydration. The resulting green oil was then purified using chromatography on a gel (ACOEL/heptane (silica 0/40) to provide the compound mentioned in the title in the form of a white solid. Step D: (4aR)-3-([2-( 4-Chlorophenyl)-5,5-dimethyl-1-cyclohexen-1-yljmethyl}-2,3,4,4a,5,6- 8 hexahydro-1H-pyrazino[1,2-a]quinoline-8 -carboxylic acid hydrochloride suspended from 0 g of step z compound in a mixture of dioxane / 1 g (Ye) HCI 11 [da ml) heated at 1 km for 000 hours . The mixture was then allowed to return to the normal temperature. 01 The resulting precipitate was filtered and then washed with diisopropyl ether and dried. The compound mentioned in the title was obtained in the form of a green solid. Preparation: Y¢ (10a[beta])-2-{[2-(4-Chlorophenyl)-5,5-dimethyl-1-cyclohexen-1 -yl]methyl}- 1,2, 3,4,10,10a-hexahydropyrazino[ 1,2-a]indole-8-carboxylic acid ([beta]=S or R) 101

ht —_— 0 _- 2-{[2-(4-Chlorophenyl)-5,5-dimethyl-1-cyclohexen-1-yl]methyl} -8-methoxy-1,2,3,4 - Tetrahydropyrazino[1,2-a]indole, then obtained in the compound of step z in preparation method 9 subject to the procedures mentioned in

2 Step B: Methyl 2-{[2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohexen-1 -yllmethyl)-1,2,3,4- tetrahydropyrazino[1,2-] a]indole-8-carboxylate The compound of step A was subjected to the procedures described in steps e, f, and in preparation method A step z= º 2-{[2-(4-Chlorophenyl)-5,5 The compound from the previous step was subjected to the procedures presented in Steps b and c in the preparation method. Step D: (10a[beta])-2-{[2-(4-Chlorophenyl)-5,5-dimethyl-1-cyclohexen-1 -yllmethyl}- Yo 1,2,3,4,10 ,10a-hexahydropyrazino[ 1,2-a)indole-8-carboxylic acid ([beta]=S or R) and then obtained the compound by separating the mixture of isomers obtained in step

Umm Jah Method of preparation: Yo (4aR)-3-{[4-(4-Chlorophenyl)-3-pyridyl]methyl}-2,3,4,4a,5,6-hexahydro-1H- pyrazino[1,2-a]quinoline-8-carboxylic acid trifluoroacetate © step | : (4-Bromo-3-pyridyl)methanol aha +. Y of us sodium borohydride was added in parts to a solution of 1 gram of 4-bromonicotinaldehyde in 5 mL of MeOH at 0 C. All stirred for 76 hours and gradually returned to normal temperature. The reaction mixture was cooled to zero; Then, the organic phases were collected. Washing was done with saturated NaCl solution; It was dried on magnesium sulphate and then concentrated to dryness. Call mentioned in the title was obtained in the form of a light brown gel Cus that was used in the next step. Step B: [4-(4-Chlorophenyl)-3-pyridylJmethanol : aha YO from aba 0.457 » Pd(Phs)y from 4-chlorophenylboronic acid then 0.5 mL of ¥ VO ¥ of aqueous 18200 solution was added sequentially to a suspension of 0.080 g of compound step A in a mixture of EtOH [DME 7 mL /mIV.©). All were degassed under argon atmosphere for V0 min and then cooled at 1 8"C for YA h. The reaction mixture was filtered at ambient temperature. The filter was then dissolved and extracted. The organic phases were collected using [0:01.

OA — - then dried on magnesium sulphate and then concentrated to dryness. The resulting substance was purified by chromatography on silica gel (J011:01/) MeOH to provide the compound given in the title. Step C: 3-(Chloromethyl)-4-(4-chlorophenyl)pyridine Yo A solution of 5460 » mL of (0.0 +A) thionyl chloride mol) in © mL of :011:01 Cah 2 added dropwise to a solution of AVR g of compound step B in 2 mL of CHCl, At a Sa all were stirred for 2 hours and gradually returned to normal temperature. The reaction mixture was then concentrated to dryness. The resulting material was jue with heptane and dried. The compound mentioned in the title was obtained in the form of a light beige solid, and it is used as is in the next step: Step d: Methyl (4aR)-3-{[4-(4-chlorophenyl)-3-pyridyl|methyl}-2,3,4,4a, 5,6-hexahydro-1H-pyrazino[1] ,2-a]quinoline-8-carboxylate The same procedure mentioned in step b in the preparation method yy + with the reaction of the compound of step i in the preparation method YY with the compound of the previous z step . Step e: (4aR)-3-{ [4-(4-Chlorophenyl)-3 -pyridyl]methyl}-2,3,4,4a,5,6-hexahydro-1H-

— 8 M pyrazino[1,2-a]quinoline-8-carboxylic acid trifluoroacetate, then subjecting the previous compound to the step J procedure in the preparation method, and an amorphous compound was obtained, as it was purified using reverse phase chromatography) YA-C ((cela scale 0yl© + 72001 from TFA). After lyophilization, the compound given in the title © was obtained in the form of TFA salt. Method of preparation ¥1: : -111-Walntra 6-112 ,2,3,4,48,5- ( Albata 101117/02 - 3-(4-0101001160271)-3-1]2-(48) pyrazino[1,2-a]quinoline-8- carboxylic acid trifluoroacetate The same procedure as in the method of preparation YO with the replacement of 4-bromonicotinaldehyde by .2-bromo-nicotinaldehyde 0 method of preparation (YY (4aR)-3-{[3-(4- Chlorophenyl)-2-pyridyljmethyl}-2,3,4,4a,5,6-hexahydro-1H- pyrazino[1,2-a]quinoline-8-carboxylic acid trifluoroacetate Same procedure as for preparation YO with 4-bromonicotinaldehyde replaced by -3-bromo-2-pyridinecarbaldehyde 0 method of preparation (YA (4aR)-3-{[3-(4-Chlorophenyl)-4-pyridylJmethyl}-2, 3,4,4a,5,6-hexahydro-1H-

— and 4 pyrazino[1,2-aJquinoline-8-carboxylic acid trifluoroacetate same procedure as in method “YO” with 4-bromonicotinaldehyde replaced by .3-bromo-isonicotinaldehyde method 9?: (4aR)-3-[(4-[(tert-Butoxycarbonyl)amino]-4'-chloro-[1,1'-biphenyl]-2-yl)methyl]- © 2,3,4,4a ,5,6-hexahydro-1H-pyrazino[1,2-a]quinoline-8-carboxylic acid Step A: Methyl 4-nitro-4'-chloro-[1,1'-biphenyl]-2-carboxylate Then, this compound was obtained using the conjugation method mentioned in Step B in the Yo Ne preparation method, with the substitution of: 4-bromo-3-pyridyl)methanol by methyl 2-bromo-5-nitrobenzoate. The expected compound was obtained after step Cleansing on (ACOEL/ petroleum ether) silica gel as a yellow solid. Step B:

4-Nitro-4'-chloro-[1,1"-biphen-2-ylJmethanol 0) was added in parts to a solution of 7.78 grams sodium borohydride of aba YY for 10 hours to 0"C. The entire mixture MeOH was stirred from 71 ml of step A compound in 1 h. The mixture of YE sad gradually returned to normal temperature, then reflux was cooled and the NHACL reaction was then cooled to zero"m; It was rehydrated using a saturated solution of organic phases and extracted using 1:01. The organic phases Yo and then the saturated magnesium sulphate concentrate were then collected; It was dried on NaCl using solution

1 1 — - to dryness. after vomiting on ACOEt/ petroleum ether (silica) gel; The expected compound was obtained as a yellow solid. Step Hd 4-Amino-4'-chloro-[1,1'-biphen-2-ylJmethanol m aba YA of stannic chloride (SnCl) was added in parts to a solution of 0. 8460 grams of step b compound in a mixture of THF (VO) mL / Yo (MeOH mL). Everyone was gradually stirred into reflux for ? hours . The reaction mixture was then concentrated to dryness; It was taken in “CH,C1, and cooled to zero 5 before (La) with 0 titer of NaOH solution and extracted using W©011:0. Then the organic phases were grouped. 0 washing was done with saturated 11801 solution; It was dried on magnesium sulphate and then concentrated to dryness. Then the expected compound was obtained in the form of a yellow solid that was used as is in the next step. Step D: 4-[(tert-Butoxycarbonyl)amino]-4'-chloro-2-(hydroxymethyl)-1,1'-biphenyl 0 1 no.. gram of BOC20 was added to a solution of 0.76 grams of compound step C in yo mL of ethanol. The whole mixture was stirred for 71 hours until it gradually reached 2270 °C. The reaction mixture was then concentrated to dryness; and was taken at 200; then dissolved and extracted with 0. The organic phases ¢ were then collected and washed with saturated NaCl solution; Magnesium sulphate was dried and then concentrated to dryness after purification

ACOE/ petroleum ether) silica gel; The compound mentioned in the title was obtained in the form of a beige solid. Step e: 4-[(tert-Butoxycarbonyl)amino]-4'-chloro-2-(chloromethyl)-1,1'-biphenyl © 877 mL of +.YY SEGN mL vo 0 YAS) mesyl chloridecse mol) were added sequentially to a solution of 0.674 g of compound from Step D in V0 mL of THF at plop saa, stirring all for 97 hours and gradually bringing to normal temperature. The reaction mixture was then concentrated to dryness. after gull on ACOEt/ petroleum ether (silica) gel; The expected compound was obtained in the form of a yellow crystalline oil. 0 step f: Methyl (4aR)-3-({4-[(tert-butoxycarbonyl)amino]-4'-chloro-[1,1'-biphenyl]-2-yl) methyl)-2 ,3,4,4a,5,6-hexahydro-1H-pyrazino[ 1,2-a]quinoline-8-carboxylate Same procedure as step b in method YF with reaction of compound step a in method YY with a compound from step EAL 0 step: (4aR)-3-[(4-[(tert-Butoxycarbonyl)amino]-4'-chloro-[ 1 '-biphenyl]-2-yl) methyl}- 2,3,4,4a,5,6-hexahydro-1H-pyrazino[ 1,2-a]quinoline-8-carboxylic acid The previous compound was subjected to the step n procedure of the NY preparation method Yo How to prepare We

- + Y — (4aR)-3-[(4-{[(tert-Butoxycarbonyl)amino}methyl}-4'-chloro-[1,1 '-biphenyl]-2- ylmethyl]-2,3,4 ,4a,5,6-hexahydro-1H-pyrazino[ 1 ,2-a]quinoline-8-carboxylic acid

Step A: Methyl 4-methoxy-4'-chloro-[1,1'-biphenyl]-2-carboxylate and then obtain this compound using the | For the conjugation mentioned in step b in the method of preparing Yo + with substitution of: (4-bromo-3-pyridyl)methanol by methyl 2-bromo-5-methoxybenzoate the expected compound was obtained as a solid after a purification step on a gel -(ACOE/ heptane ( silica) Step B: 1 Methyl 4'-chloro-4-hydroxy-[1,1'-biphenyl}-2-carboxylate 0 1 M solution of 313:3 in £Y mL of :11:01© i was added slowly to a solution of 101g of compound step A in 001 mL of CHCl at -/laTm. Stirred at said temperature for 1 hour 10 minutes A mixture of 1120/MeOH (£4mL/01mL) was added next. The entire mixture was stirred at £0 min at -/7*C; Then it was extracted using CHCl, then the organic phases were collected and dried on magnesium sulphate before concentration to dryness. Ay foam was obtained and used in the next step. Step C: Methyl 4'-chloro-4-trifluoromethanesulphonyl-[1,1 '-biphenyl]-2-carboxylate

— $1 —; mL of (Use ror YA)EGN and .1 gram of : (N-phenyl-bis(trifluoromethanesulphonamide) diluted sequentially to a solution of #01 grams of compound step B in da 1 of CH,CL at zero a. Then all were stirred for 01 dele time and gradually shifted to normal temperature. The reaction mixture was then concentrated to dryness and taken in 80084 and taken sequentially in solution 1 HCL titer, saturated NaHCO solution and saturated NaCl solution, then dried on magnesium sulphate After purification on heptane gel (silica /: 2008), the expected compound was obtained in the form Colorless oil. Hazardous d: Methyl 4'-chloro-4-cyano-[1,1'-biphenyl]-2-carboxylate pha ..44 Ne of 0.0156 Pd2(dba)3 gram of 0.477 5 dppf gram of Zn(CN)2 was added sequentially to a solution of pha 017 of compound step C in +5 mL of 1147. All was stirred for − hours until it gradually reached 16 C The Jeli mixture was then concentrated and taken into ACOEt ¢ sequentially with a saturated LiCl solution and a saturated NaCl solution before drying it on magnesium sulphate. After purification on an ACOELt/heptane (heptane) silica gel ); The expected compound was obtained in the form of a colorless, gradually crystalline oil. Step E: Methyl 4-aminomethyl-4'-chloro-[1,1'-biphenyl]-2-carboxylate

0 : 04 grams of 141012 and 9710 grams of sodium borohydride were added in parts to a suspension of aba YOY from compound of step D in 660 mL of MeOH at 0”C. All stirred for 7 hours and gradually switched to normal temperature. The reaction mixture was then filtered; The filtrate was diluted with: 0015 M before being hydrolyzed. The organic phases© were then grouped; Washing was done with saturated NaCl solution; It was dried on magnesium sulphate and then concentrated. The compound mentioned in the title was obtained in the form of white foam and was used in the next step. step f: . Methyl 4-{[(tert-butoxycarbonyl)amino]methyl}-4'-chloro-[1,1 '-biphenyl]-2-carboxylate pha Y.AY 0 from BOC20 was added to a solution of 7.07 grams of step E compound in 0 mL of 1:01. Then the whole mixture was stirred at ambient temperature for 1 hour. The reaction mixture was then concentrated to dryness. after 4800 on a silica (petroleum ether / 00121) gel; The compound mentioned 1 in the title was obtained in the form of a white solid. Step g: 4-{[(tert-Butoxycarbonyl)amino }methyl} -4'-chloro-2-(hydroxymethyl)-1,1'-biphenyl Y14Y

— 9 1 — 4 molar solution of os THF 3 LAH added dropwise to a solution of 0.6 g of step compound and at zero m in 0 mL of THF . then stirred thoroughly at ambient temperature for 2 hours . dale) The reaction mixture was then purified with a saturated solution of RoCHelle salt at ambient temperature for 1 hour 0 ? minute. Then the extraction 2 was done using ACOEt, then the organic extracts were collected ¢ and washed with a saturated NaCl solution and dried on magnesium sulphate and then concentrated to dryness. after purification on ACOEt/ petroleum ether (silica) gel; The compound mentioned in the title was obtained in the form of a transparent oil. Step h: 4-{[(tert-Butoxycarbonyl)amino]methyl}-4'-chloro-2-(chloromethyl)-1,1'-biphenyl Ve 7 mL of veer ART JEGN mol) and + .0Y ml of mesyl chloride (.777 mol) was added sequentially to a solution of 0.96 g of compound step g in 580 ml of THF at 0 C. All stirred for 97 hours and gradually returned to normal temperature. The reaction mixture was then concentrated to dryness. After purification on “(ACOEY/ petroleum ether) silica gel. Ve to obtain the expected compound in the form of crystalline oil. Step i: Methyl (4aR)-3-1(4-{[(tert-butoxycarbonyl)amino]methyl} -4'-chloro-[ 1,1 -biphenyl]-2- ylmethyl]-2,3 ,4,4a,5,6-hexahydro-1H-pyrazino[ 1,2-a]quinoline-8 -carboxylate

Vv_l_ the same procedure as described in Step B in preparation YY with the reaction of compound of Step A in preparation YY with a compound from the previous step h. Then obtaining the compound mentioned in the title after a purification step on -(ACOEt/ heptane) silica gel step j: (4aR)-3-[(4-{[(tert-Butoxycarbonyl)amino]methyl}-4'- chloro-[1,1'-biphenyl]-2-©yDmethyl]-2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-a]quinoline-8-carboxylic acid Then exposing the previous compound to the step n procedure in the preparation method ensured that the expected compound was obtained in the form of a white solid. 1,1'-biphenyl]-2-yl)methyl]-2,3,4,4a,5,6-hexahydro-1H- 01 pyrazino[1,2-a]quinoline-8-carboxylic acid step A : Methyl (4aR)-3-(2-bromobenzyl)-2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-a]quinoline-8-carboxylate Ve Same procedure as described in Step B in YY preparation method with Jeli Compound Step A in YY preparation method using -1-bromo-2-(bromomethyl)benzene Step B:

A - - Methyl (4aR)-3-[(3'-fluoro-4'-chloro-[1,1'-biphenyl]-2-yl)methyl]-2,3,4,4a,5 ,6- hexahydro-1H-pyrazino[1,2-a]quinoline-8-carboxylate The same procedure mentioned in step b in the “YO” preparation method with the substitution of: 4-chlorophenylboronic acid by 3- fluoro-4-chlorophenylboronic acid . © Step C: (4aR)-3-[(3'-Fluoro-4'-chloro-[1,1'-biphenyl]-2-yl)methyl}-2,3,4,4a,5,6 -hexahydro-1H- pyrazino[1,2-aJquinoline-8-carboxylic acid The previous compound was subjected to the step n procedure of preparation method AY method of preparation YY a (4aR)-3-[( 4'-Cyano-[1,1"-biphenyl]-2-yl)methyl]-2,3,4,4a,5,6-hexahydro-1H- Vo pyrazino[1,2-a]quinoline- 8-carboxylic acid The same procedure mentioned in the method of preparation YY with acetydal: 3-fluoro-4-chlorophenylboronic acid in step b by 4-cyanoboronic acid + 10 method of preparation WY (4aR) -3-[(4"-Trifluoro-{1,1'-biphenyl]-2-yl)methyl]-2,3,4,4a,5,6-hexahydro-1 H- pyrazino[1,2] -a]quinoline-8-carboxylic acid

Same procedure as for preparation “VY” with replacement 0216010016 110010-4-0110:00- 3Avi step b using -4-trifluoromethylboronic acid method for preparation Ve (4aR)-3-[2-(1,3-) Benzodioxol-5-yl)benzyl]-2,3,4,4a,5,6-hexahydro-1 H-pyrazino[1,2- aJquinoline-8-carboxylic acid 8 The same procedure as mentioned in the preparation method « VY with 3-fluoro-4-chlorophenylboronic 0 replaced in step b with 1,3-benzodioxol-5-ylboronic acid. Method of preparation (Ye (4aR)-3-Benzhydryl-2,3 ,4,4a,5,6-hexahydro-1H-pyrazino[ 1,2-a]quinoline-8-carboxylic acid Yo Step A: Methyl (4aR)-3-benzhydryl-2,3,4, 4a,5,6-hexahydro-1H-pyrazino[ 1,2-a]quinoline-8- carboxylate 0 Same procedure as step b in method YY with reaction of compound step a in method YY using 0 [bromo(phenyl)methyl]benzene step b:

- and (4aR)-3-Benzhydryl-2,3,4,4a,5,6-hexahydro-1H-pyrazino[ 1,2-a]-quinoline-8-carboxylic acid, then exposing the previous compound To the procedure for step n in the method of preparation RY Preparation method WY ° -111-WeblinRittalh©2,3,4,48,5,6-1- (Al-Bataa [eng.1zm-3-(4-0110100160271) )-3-114-(485,14) pyrazino[1,2-a]quinoline-8-carboxylic acid trifluoroacetate The same procedure mentioned in the method of preparation Yo in step d with the replacement of the compound of step a in method of preparation ra using The mixture of isomers from step z in preparation method 1 Preparation method: Yv.(4aS,R)-3-{[4-(4-Chlorophenyl)-3-pyridyljmethyl}-2,3,4 ,4a,5,6-hexahydro-1H- Ve pyrazino[1,2-a]quinoline-8-carboxylic acid trifluoroacetate Same procedure as YT preparation in step d with substitution of step a compound in method yy using the compound of step z in the method of preparation a Yo the method of preparation YA (4aS,R)-3-{[3-(4-Chlorophenyl)-2-pyridyl]methyl}-2 ,3,4,4a,5,6-hexahydro-1H- pyrazino[ 1,2-a]quinoline-8-carboxylic acid trifluoroacetate

1 1 _ - the same procedure as described in preparation YY in step D with the substitution of the compound of step A in preparation YY by using the compound of step H in preparation A Method of preparation 9?: (4aS,R )-3-{[3-(4-Chlorophenyl)-4-pyridylJmethyl}-2,3,4,4a,5,6-hexahydro-1H- pyrazino[1,2-a]quinoline-8-carboxylic acid trifluoroacetate 8 Same procedure as in preparation YA in step d with the substitution of the compound of step a in preparation Yy with the compound of step z in preparation 1 preparation tn (4aS,R)-3 -[(2-(4-Pyridyl)-3-pyridyl)methyl]-2,3,4,4a,5,6-hexahydro-1H-pyrazino[ 1,2-a]quinoline-8-carboxylic acid trifluoroacetate Ve Same procedure as in method for preparation (YO) using 2-bromo-nicotinaldehyde in step 4-pyridylboronic acid 0 i in step b in step d; using the mixture of coenomers from step h in method 1 as tricyclic synthon Yo. Method of preparation) 16 (4aS,R)-3-[(2-(6-Chloro-pyrid-3-yl)-3-pyridyl)methyl]-2,3, 4,4a,5,6-hexahydro-1H- pyrazinof1,2-a]quinoline-8-carboxylic acid trifluoroacetate

-V Y -— same procedure as in method for preparing (Yo) using 2-bromo-nicotinaldehyde in step a, 6-chloro-3-pyridylboronic acid in step b, step d; using the mixture of isomers from step H in method 1 k tricyclic synthon method 67 : (4aS,R)-3-[(2-(6-Hydroxy-pyrid-3-yl)-3-pyridyl)methyl]-2, 3,4,4a,5,6-hexahydro-1H-© pyrazino[1,2-aJquinoline-8-carboxylic acid trifluoroacetate] Same procedure as for preparation (Yo) using 2-bromo-nicotinaldehyde in Step A, 6-hydroxy-3-pyridylboronic acid in Step B, Step D, using the mixture of isomers from Step H in preparation method 1 as tricyclic synthon.Ye Method of preparation: 2-{[ 2-(4-Chlorophenyl)-3-pyridyl]methyl}-1,2,3,4-tetrahydro-pyrazino[ 1,2-a]indole-8- carboxylic acid trifluoroacetate The same procedure mentioned in the preparation method (Yo using 2-bromo-nicotinaldehyde in step 4-chlorophenylboronic acid f in step b in step d using step compound and in Vo preparation method 4 as tricyclic synthon . Preparation method: 2-{[2-(6-Chloro-pyrid-3-yl)-3-pyridyllmethyl}-1,2,3,4-tetrahydropyrazinof 1 ,2-ajindole- 8-carboxylic acid trifluoroacetate ‏

vy — _— same procedure as in method for preparation (YO) using 2-bromo-nicotinaldehyde in step 6-chloro-3-pyridylboronic acid « j in step b in step d; using compound of step f Preparation: 4 tricyclic synthon S. Preparation 2 (4aS,R)-3-[(4'-tert-Butyl-[1,1'-biphenyl]-2-yl)methyl]-2, 3,4,4a,5,6-hexahydro-1H- © pyrazino[1,2-a]quinoline-8-carboxylic acid Same as J for procedure mentioned in Sun + method with substitution: 3-fluoro -4-chlorophenylboronic acid in step B using: 4-tert-butyl-phenylboronic acid E and in step C using the mixture: methyl (4aS,R)-2,3,4,4a,5,6-hexahydro- 1H-pyrazino[ 1,2-a]quinoline-8-carboxylate Ve (step z in preparation method 1) instead of: methyl (4aR)-2,3,4,4a,5,6- hexahydro-1H-pyrazino[1,2-a]quinoline-8-carboxylate (step a in preparation method (YY 1 axial method) to prepare 5: (4aS,R)-3-[ 2-(4-Chlorobenzyl)benzyi]-2,3,4,4a,5,6-hexahydro-1 H-pyrazino[ 1,2- aJquinoline-8-carboxylic acid Same as for the procedure mentioned in the method of preparation 3 in step 1 with replacement:

Vv — - 4-chloro-2'-(chloromethyl)-1,1'-biphenyl using: 1-chloro-2-(4-chlorobenzyl)benzene . Preparation 497 : 3-(2-Phenoxybenzyl)-2,3,4,4a,5,6-hexahydro-1H-pyrazino[ 1,2-a]quinoline-8-carboxylic acid 5 Step A: Methyl 3-(2-phenoxybenzyl)-2,3,4,4a,5,6-hexahydro-1H-pyrazino[ 1,2-a]quinoline-8-carboxylate, the compound of step H in the method of preparation 1 was subjected to reductive amination 0 by reacting with 2-phenoxybenzaldehyde in the presence of 3). The reaction mixture was then treated with acetic acid and then extracted with -CHyCI, step b: 3-(2-Phenoxybenzyl)-2,3,4,4a,5,6-hexahydro-1H-pyrazino [1,2-a]quinoline-8-carboxylic acid The same procedure mentioned in step j in preparation method 1. Example No. 1: N-({(4aS,R)-3 -[(4'-Chloro-[1,1"-biphenyl]-2-yl)methyl]-2,3,4,4a,5,6-hexahydro-1H- pyrazino[1,2-a] quinolin-8-yl} carbonyl)-4-{(1R)-3-(dimethylamino)- 1 - Ye

~~[(phenylsulphanyl)methyl]propyl}amino)-3-nitrobenzenesulphonamide bistrifluoroacetate Step A: N-({(4aS,R)-3-[(4'-Chloro-[1,1 "-biphenyl]-2-yl)methyl]-2,3,4,4a,5,6-hexahydro-1H- pyrazino[1,2-a]quinolin-8-yl} carbonyl)-4-( {(1R)-3-(dimethylamino)-1- 2 [(phenylsulphanyl) methyl]propyl } amino)-3-nitrobenzenesulphonamide 5..? ml of DIEA then 010 grams of: 4- (((1R)-3-(dimethylamino)-1-[(phenylsulphanyl)methyl]propyl }amino)-3- nitrobenzenesulphonamide Ye then aha YAY from EDC 0.+g of DMAP were added at ambient temperature to a solution of 0.716 g obtained in a method compound of 1 in 0 mL of a mixture of 1117(1/1)/0112012. The reaction mixture was stirred at ambient temperature for two days.The resulting residue was evaporated to dryness and then the resulting residue was taken into a saturated solution of NHACL and the extraction was performed twice with CH,CL.Jue the organic phase was done with a saturated NaCl solution of 05 and then Dried on a “MgSCU” filtration was performed and evaporated to dryness. The resulting oil was purified using flash chromatography on silica gel (0.1). 6/1/8 4 NH4OH/MeOH/CH2CI2) and then lyophilized for the compound given in the title in the form of yellow alia elemental microanalysis:

— 1 7 _ tn |e | step b: N-({(4aS,R)-3-[(4'-Chloro-[1,1'-biphenyl]-2-yl)methyl]-2 ,3,4,4a,5,6-hexahydro-1H- pyrazino[1,2-a]quinolin-8-yl} carbonyl)-4-({(1R)-3-(dimethylamino)-1- [(phenylsulphanyl)methyl]propyl} amino)-3-nitrobenzenesulphonamide 2 bistrifluoroacetate obtained in compound step A (07 g) was dissolved in 0 mL of CHCl at 0 ta Then (£.Y)©) trifluoroacetic acid was added dropwise. The whole mixture was then stirred at ambient temperature for 0 ? min to dry the concentrate. The resulting material was then taken into CHCN sole Ve, added dropwise to the complete dissolution of the reaction mixture, and then lyophilized at low temperature for ; ? hour . Then obtaining a solid, yellow, wool-like material that corresponds to the compound mentioned in the title. Example ¥ : N-({(4aS,R)-3-[(4'-Chloro-[1,1'-biphenyl]-3-yl)methyl]-2,3,4,4a,5 , 6-hexahydro-1H- \o pyrazino[1,2-a]quinolin-8-yl} carbonyl)-3-nitro4-{[2-(phenylsulphany!))

A ethyllamino} benzenesulphonamide hydrochloride: Step A

N-({(4aS,R)-3-[(4'-Chloro-[1,1'-biphenyl]-3-yl)methyl]-2,3.4,4a,5,6-hexahydro-1H-pyrazino [1,2-a]quinolin-8-yl} carbonyl)-3-nitro-4-{[2-(phenylsulphanyl) ethylJamino} benzenesulphonamide 8 1 with compound substitution in method of preparation 10 Same procedure as in step a From Example No.: With the compound given in preparation method for 6 and with the replacement of 4-({(1R)-3-(dimethylamino)-1-[(phenylsulphanyl)methyl]propyl }amino)-3- nitrobenzenesulphonamide -3-nitro -4-{[2-(phenylsulfanyl)ethyl]amino} benzenesulphonamide using 0 : for step B J

N-({(4aS,R)-3-[(4'-Chloro-[1,1'-biphenyl]-3-yl)methyl]-2,3,4,4a,5,6-hexahydro-1H - pyrazino [1,2-a]quinolin-8-yl]carbonyl)-3-nitro-4- {[2-(phenylsulphanyl) ethylJamino)benzenesulphonamide hydrochloride yo ml of :011:01 at 01 was obtained In step A compound (0.7 g) was dissolved in µL (7725) (MY) 5100 was added in hydrochloric acid and then a solution of ca' hua dropwise. The whole mixture was then stirred at ambient temperature for 0 minutes;and then

VA - - Concentrate to dryness. The resulting material was then taken into water and CH3CN added dropwise until complete dissolution from the reaction mixture; Then it was lyophilized at low temperature for ; 1 hour example number? : N-({(4aS,R)-3-[(4'-Chloro-[1,1'-biphenyl]-4-yl)methyl]-2,3,4,4a,5,6-hexahydro -1H- 8 pyrazino[1,2-a]quinolin-8-yl)carbonyl)-3-nitro-4-{[2- (phenylsulfanyl) ethyl] amino }benzenesulphonamide hydrochloride Step A: N -({(4aS,R)-3-[(4'-Chloro-[1,1'-biphenyl]-4-yl)methyl]-2,3,4,4a,5,6-hexahydro-1H- pyrazinof 1,2-a]quinolin-8-yl}carbonyl)-3-nitro-4- {[2-(phenylsulphanyl)ethyl] 01 amino } benzenesulphonamide Same procedure as in step from example pe ) Substituting a compound in preparation method 1 with the compound in preparation oF and substituting 4-({(1R)-3-(dimethylamino)-1-[(phenylsulphanyl)methyl}propyl} amino)- 3- Nitrobenzenesulphonamide Yo using: 3-nitro-4-{[2-(phenylsulphanyl)ethyl]Jamino} benzenesulphonamide Step: 3-nitro-4-{[2-(phenylsulphanyl)ethylJamino} benzenesulphonamide. Same procedure as in step b of Example Yd) Example 6: N-({(4aS,R)-3-[(4'-Chloro-[1,1'-biphenyl]-4-yl) methyl]-2,3,4,4a,5,6-hexahydro-1 H- Ye Yiay

ve - - pyrazino[1,2-a]quinolin-8-yl} carbonyl)-3-nitro-4-{[2-(phenylsulphanyl) ethyllamino } benzenesulphonamide hydrochloride Step A: N-{ [(4aS,R)-3-[1,1"-Biphenyl]-2-ylmethyl)-2,3,4,4a,5,6-hexahydro- 1H-pyrazino[ 1,2-a]quinolin-8 -yljcarbonyl}-4-({(1R)-3-(dimethylamino)-1-[(phenylsulphanyl) 5 ‎methyl]propyl}amino)-3-nitrobenzenesulphonamide bis(hydrochloride) Same procedure as in Step A of example no. geo) Compound Substitution in Preparation Method 1 Elemental Microanalysis: Ye No Cos pow [ow Step B: N-{[(4aS,R)-3-([1,1 '-Biphenyl]-2-ylmethyl)-2,3,4,4a,5,6-hexahydro-1 H-pyrazino[1,2- aJquinolin-8-yl]carbonyl)-4-({(1R) )-3-(dimethylamino)- 1 -[(phenylsulphanyl) methyl]propyl}amino)-3-nitrobenzenesulphonamide Yo same | for the procedure mentioned in step b of example number CY Yay

A+ — - Elemental Microanalysis: Deposit an Lae a ae Example 0: N-{[(4aS,R)-3-2-Benzylbenzyl)-2,3,4,4a,5 ,6-hexahydro-1H-pyrazino[1,2-a]quinolin-8- yl]carbonyl} -3-nitro-4-{[2-(phenyl-sulphanyl)ethyl]amino} benzenesulphonamide © hydrochloride Step A: N-{[(4aS,R)-3-(2-Benzylbenzyl)-2,3,4,4a,5,6-hexahydro-1H-pyrazino[ 1,2-a]quinolin- 8- yl]carbonyl}-3-nitro-4-{[2-(phenylsulphanyl)ethyl]-amino}benzenesulphonamide 0 Same procedure as in Step A of Example 0; with compound substituted in method of preparation 1 Using a compound in the preparation method ©« and with the replacement of: 4-({(1R)-3~(dimethylamino)-1-[(phenylsulphanyl)methyl}propyl }amino)-3- nitrobenzenesulphonamide using 3-nitro-4-{[2-(phenylsulfanyl)ethyl]amino}benzenesulphonamide.:

A 1 _ - Step B: N-{[(4aS,R)-3~(2-Benzylbenzyl)-2,3,4,4a,5,6-hexahydro-1H-pyrazino[ 1,2- a]quinolin-8- yl]carbonyl}-3-nitro-4-{[2-(phenylsulphanyl)ethyl]-amino} benzenesulphonamide hydrochloride © Same as J for procedure in Step B of Example No. 1 Example 1: 3-Nitro-N-{(4aS,R-3-[2-(2-phenylethyl)benzyl]-2,3,4,4a,5,6-hexahydro-1H- pyrazino[1,2-a]quinolin-8-yl} carbonyl)-4-{[2-(phenylsulphanyl)-ethyl] amino } benzenesulphonamide 0 Same procedure as in Step A of Example 1 With the replacement of a compound in preparation method 1 using the compound given in preparation method oT and with the replacement of: 4-({(1R)-3-(dimethylamino)-1-[(phenylsulphanyl)methyl]propyl}amino )-3- nitrobenzenesulphonamide by 3-nitro-4-{[2-(phenylsulphanyl)ethyl] amino} benzenesulphonamide.Yo Elemental microanalysis:

A Y — — 000 | :qa#a| «A | Example 7: N-({(4aS,R)-3-[(4'-Chloro-[1,1 "-biphenyl}-2-yl)methyl]-2,3 .4,4a,5, 6-hexahydro-1H- pyrazino[1,2-a]quinolin-8-yl} carbonyl)-3-nitro4- {[2- (phenylsulphany]) ethyl] amino } benzenesulphonamide © Same procedure as in Step A of example ae) replace : 4-({(1R)-3-(dimethylamino)-1 -[(phenylsulphanyl)methyl]propyl }amino)-3- nitrobenzenesulphonamide with -3 nitro-4-{[2-(phenylsulfanyl)ethylJamino} benzenesulphonamide elemental microanalysis: 0.1 was

AY -— — Example tA N-({(4aS,R)-3-[(4'-Chloro-[1,1'-biphenyl]-2-yl)methyl]-2,3 ,4,4a,5,6-hexahydro-1H- pyrazino[1,2-a]quinolin-8-yl)carbonyl)-3-nitro-4-[(2-phenoxyethyl)amino] enzenesulphonamide © Same procedure as in Step A of example ae) Substituting: N-{[(4aS,R)-3-([1,1'-Biphenyl}-2-ylmethyl)-2,3,4 ,4a,5,6-hexahydro-1H-pyrazino[1,2- ajquinolin-8-yl]carbonyl)-3-nitro-4-[(3-phenylpropyl)-amino]benzenesulphonamide Elemental microanalysis: [ow Jum] ee [0 0 > Ex. 14d) N-{[(4aS,R)-3-([1,1"-Biphenyl}-2-ylmethyl)-2,3, 4,4a,5,6-hexahydro-1H-pyrazinof1,2- aJquinolin-8-yl]carbonyl)-3-nitro-4-[(3-phenylpropyl)-amino]benzenesulphonamide Same procedure as in step a From Example 1; with the compound obtained in preparation method 1 replaced by the compound obtained in preparation of and with 0 substituted: 4-({(1R)-3-(dimethylamino) )-1-[(phenylsulfanyl)methyl]propyl} amino)-3- nitrobenzenesulphonamide

A ¢ — _ Using: 3-nitro-4-[(3-phenylpropyl)amino]benzenesulphonamide Elemental microanalysis: D only A Example 0: 4-[(2-Anilinoethyl)amino }-N-{[(4aS,R)-3 -([1,1-biphenyl]-2-ylmethyl)-2,3,4,4a,5,6- 5 hexahydro-1H-pyrazino[1,2] -a]quinolin-8-yl]carbonyl)-3-nitrobenzenesu Iphonamide Same procedure as in Step A of Example 1; replacing the compound obtained in preparation method 1 with the compound obtained in preparation method of and with the replacement: 4-({(1R)-3-(dimethylamino)-1 -[(phenylsulphanyl)methyl]propyl } amino)-3- Ye nitrobenzenesulphonamide using 4-[(2- anilinoethyl)amino]-3-nitrobenzenesulphonamide Elemental microanalysis: E7 Cn am

— M A _— Example No.: N-{[(4aS,R)-3-[1,1 -Biphenyl]-2-ylmethyl)-2,3,4,4a,5 ,6-hexahydro- 1H-pyrazino[1,2- aJquinolin-8-yljcarbonyl}-4-{[3 -(dimethylamino)propyl]-[2- (phenylsulphanyl)ethyl]amino }-3-nitrobenzenesulphonamide hydrochloride © Step A : N-{[(4aS,R)-3-([1,1 -Biphenyl]-2-yImethyl)-2,3,4,4a, 5,6-hexahydro-1H-pyrazino[1,2-] aJquinolin-8-yl]carbonyl}-4-{[3 -(dimethylamino)propyl] [2-(phenylsulphanyl)ethyl] amino}-3-nitrobenzenesulphonamide Same procedure as in Step A of Example No. 1 with the replacement of the compound 01 obtained in the preparation method 1 with the compound obtained in the preparation method ; ¢ and substituting: 4-({(1R)-3 ~-(dimethylamino)-1- [(phenylsulphanyl)methyl]propyl }amino)-3- nitrobenzenesulphonamide by: 4-{[3-( dimethylamino)propyl] [2-(phenylsulphanyl)ethylJamino }-3-nitrobenzene-Vo sulphonamide.

A 1 - — Step B: N-{[(4aS,R)-3-([1,1'-Biphenyl]-2-ylmethyl)-2,3,4,4a,5,6-hexahydro - 1 H-pyrazino[ 1,2- a]quinolin-8-yljcarbonyl}-4-{[3-(dimethylamino)propyl][2-phenylsul phanyl) ethylJamino}-3-nitrobenzenesulphonamide hydrochloride © same | To perform the procedure described in Step B of the Elemental Microanalysis Example Number: IRR Example Number VY N-({(4aS,R)-3-[(4'-Chloro-[1,1-biphenyl]- 2-yl)methyl]-2,3,4,4a,5,6-hexahydro-1H- pyrazinof 1,2-aJquinolin-8-yl} carbonyl)-4-{[3-(dimethylamino)propylJamino} -3- Ve nitrobenzenesulphonamide Same procedure as in Step A of example peo) Substituting: 4-({(1R)-3-(dimethylamino)- 1-[(phenylsulphanyl)methyl]propyl } amino )-3- nitrobenzenesulphonamide 0 using: 4-{[3-(dimethylamino)propylJamino}-3-nitrobenzenesulphonamide.

A Vv — _ Elemental Microanalysis: Jae | A L Example No. DAY N-({(4aS,R)-3 -[(4'-Chloro-[1,1 ~biphenyl]-2) -yl)methyl]-2,3,4,4a,5,6-hexahydro- 1H- pyrazino[1,2-a]quinolin-8-yl} carbonyl)benzene-sulphonamide 8 Same procedure as in step a From Example 1; substituting: 4-({(1R)-3-(dimethylamino)-1 -[(phenylsulphanyl)methyl]propyl }amino)-3- nitrobenzenesulphonamide with 0 benzene sulphonamide 0 elemental microanalysis: general a ol

— AA —_

: 01 Example 4-{[(2-Aminoethyl)(2-phenylethyl)amino]methyl)-N-{(4aS,R)-3-[(4'-chloro-[1,1'- biphenyl) ]-2-yl)methyl]-2,3,4,4a,5,6-hexahydro-1H-pyrazino-[ 1,2-a]quinolin-8- yl)carbonyl)benzenesulphonamide tris(trifluoroacetate)

Step 2a : 4-{[(2-Aminoethyl)(2-phenylethyl)amino]methyl} -N-({(4aS,R)-3-[(4'-chloro-[1,1'- biphenyl]-2-yl)methyl]-2,3,4,4a,5,6-hexahydro-1H-pyrazino[ 1,2-a]quinolin-8- yl} carbonyl)benzenesulphonamide : with substitution + 1 For the procedure mentioned in Step A of Example No. 1, the same 4-({(1R)-3-(dimethylamino)-1-[(phenylsulphanyl)methyl]propyl ( amino)-3- Ve nitrobenzenesulphonamide: using 4-{[(2-amino-ethyl)(2-phenylethyl)amino]methyl} benzenesulphonamide. : Step B 4-{[(2-Aminoethyl)(2-phenylethyl)amino]methyl} -N- (((4aS,R)-3-[(4'-chloro-[1,1'- \o biphenyl]-2-yl)methyl]-2,3,4,4a,5,6-hexahydro- 1 H-pyrazino[ 1,2-a]quinolin-8- yl}carbonyl)benzenesulphonamide tris(trifluoroacetate)

- Do the same as 1 for the procedure mentioned in Step B of Example No. A Elemental Microanalysis: EET TET ET Example No. 01: N-({(4aS,R)-3-[( 4'-Chloro-[1,1'-biphenyl]-2-yl)methyl]-2,3,4,4a,5,6-hexahydro-1H- 2 pyrazinol[1,2-a]quinolin- 7-yl} carbonyl)-4-({(1R)-3-(dimethylamino)-1- [(phenylsulphanyl)methyl]propyl } amino)-3-nitrobenzenesulphonamide Same procedure as in Step A of Example No. ) With the replacement of the compound that was obtained in preparation method 1 with compound A $@ and then obtained in preparation method RR elemental microanalysis: ERNE

Example: N-{[(4aS,R)-3-([1,1'-Biphenyl]-2-ylmethyl)-2,3.4,4a,5,6-hexahydro-1H-pyrazino[1,2] - aJquinolin-7-yl]carbonyl}-4-({(1R)-3-(dimethylamino)-1-[(phenylsulphanyt) methyl]propyl}amino)-3-nitrobenzenesulphonamide © Same procedure as above In Step A of Example No. oY replacing the compound obtained in preparation method 1 with the compound obtained in preparation method

A

A+0.YY +1 :z [Theoretic m

AvO.YY VY :z/Measured m : 117 Example 0

N-{[2-[1,1'-Biphenyl]-2-ylmethyl)-1,2,3,4-tetrahydropyrazino[ 1,2-a]indol-8-yl]carbonyl)-4-({( 1R)-3-dimethylamino)-1-[(phenyl-sulphanyl)methyl]propyl } amino)-3- nitrobenzenesulphonamide bis(hydrochloride): Step A

N-{[2-([1,1'-Biphenyl]-2-ylmethyl)-1,2,3,4-tetrahydropyrazino[ 1.,2-2[10001-8- Yo yl]carbonyl}-4- (((1R)-3-(dimethylamino)-1-[(phenylsulphanyl)methyl]-propyl} amino)- 3-nitrobenzenesulphonamide

q 1 — _ the same procedure as in step a of the oad example) substituting the compound obtained in preparation method 1 with the compound obtained in preparation LA step b: N-{ [2-([1,1'-Biphenyl]-2-ylmethyl)-1,2,3,4-tetrahydropyrazino[ 1,2-a}indol-8- yljcarbonyl}-4-({(1R) -3-(dimethylamino)-1-[(phenylsulphanyl)methyl]-propyl } amino)- 8 3-nitrobenzenesulphonamide bis(hydrochloride) Same procedure as in Step B of Example Y Example 18: N-({2-[(4'-Chloro-[1,1'-biphenyl}-2-yl)methyl]-1,2,3,4-tetrahydro-pyrazino[ 1,2-a]indol- 8-yl}carbonyl)4-({(1R)-3-(dimethylamino)-1-[(phenylsulphanyl)methyl]propyl } amino)- Ye 3-nitrobenzenesulphonamide bis(hydrochloride) Step A: N-({2-[(4'-Chloro-[1,1'-biphenyl]-2-yl)methyl]-1,2,3,4-tetrahydro-pyrazino[1,2-a]indol- 8-yl}carbonyl)-4-({(1R)-3-(dimethylamino)-1-[(phenylsulphanyl)methyl]propyl}amino)- 3-nitrobenzenesulphonamide : 1 Same procedure as in Step A of Example 1; with the replacement of the compound obtained in preparation method 1 with the compound obtained in preparation oe step b: -1,1,2-8[1000 N-({2-[( 4'-Chloro-[1,1'-biphenyl]-2-yl)methyl]-1,2,3,4-tetrahydro-pyrazino[

- 97 - 8-yl}carbonyl)-4-({(1R)-3-(dimethylamino)-1-[(phenylsulphanyl)methyl]propyl}amino)- 3-nitrobenzenesulphonamide bis(hydrochloride)

same | To do in Step B of Example X Example 4: N-({(10aS,R)-2-[(4'-Chloro-[1,1'-biphenyl]-2-yl)methyl ]-1,2,3,4,10,10a- 8 hexahydropyrazino[1,2-a]indol-8-yl} carbonyl)-4-({(1R)-3-dimethyl-amino)-1 [(phenylsulphanyl)methyl]propyl}amino)-3-nitrobenzene-sulphonamide Same procedure as in Step A of Example 1, with the compound obtained in preparation method 1 replaced by compound S $ Then get it in preparation method A) Ye Elemental microanalysis: as | oan [ae [re | Example number Yo: N-({(4aR)-3-[(4'-Chloro-[1,1'-biphenyl]-2-yl)methyl]-2,3 ,4,4a,5,6-hexahydro-1H- pyrazino]1,2-a]quinolin-8-yl} carbonyl)-4-({(1R)-3-(dimethylamino)-1-

— {yy - [(phenylsulphanyl)methyl]propyl}amino)-3-nitrobenzenesulphonamide bis(hydrochloride) Step A : N-({(4aR)-3-[(4'-Chloro-[1,1'-biphenyl) ]-2-yl)methyl]-2,3,4,4a,5,6-hexahydro-1H- pyrazino[1,2-a]quinolin-8-yl}carbonyl)-4-({(1R) )-3-(dimethylamino)-1- 5 [(phenylsulphanyl)methyl]propyl}amino)-3-nitrobenzenesulphonamide Same procedure as in step a of example number ge) Substituting the obtained compound 1: Micro-elemental analysis ye

EEE ETERERS

Step b

N-({(4aR)-3-[(4'-Chloro-[1,1'-biphenyl]-2-yl)methyl]-2,3.4,4a,5,6-hexahydro-1H-pyrazino[ 1 ,2-a]quinolin-8-yl}carbonyl)-4-({(1R)-3-(dimethylamino)-1-

Yay

ْ - 96 - [(phenylsulphanyl)methyl]propyl}amino)-3-nitrobenzenesulphonamide bis(tehydrochloride) Same procedure as in step b of example Yad) Elemental microanalysis: o rel ae | Aqa Example No. 1: N-({(4aS)-3-[(4'-Chloro-[1,1'-biphenyl}-2-yl)methyl]-2,3,4,4a,5 ,6-hexahydro-1H- pyrazino[1,2-a]quinolin-8-yl} carbonyl)-4-({(1R)-3-(dimethylamino)-1- [(phenylsulphanyl)methyl] propyl}amino)-3-nitrobenzenesulphonamide bis(hydrochloride) 01 Step A: N-({(4aS)-3-[(4'-Chloro-[1,1'-biphenyl]-2-yl) methyl}-2,3,4,4a,5,6-hexahydro-1H-

A 40 - ‎pyrazino[ 1,2-a]quinolin-8-yl} carbonyl)-4-({(1R)-3-(dimethylamino)-1- [(phenylsulphanyl)methyl]propyl}amino)- 3-nitrobenzenesulphonamide Same procedure as in Step A of Example 10 with the compound obtained substituted

in preparation method 1 with the compound obtained in preparation AY © step b: N-({(4aS)-3-[(4'-Chloro-[1,1'-biphenyl]-2 -yl)methyl]-2,3,4,4a,5,6-hexahydro-1H- pyrazino[1,2-alquinolin-8-yl} carbonyl)-4-({(1R)-3-( dimethylamino)-1- [(phenylsulphanyl)methy!l] propyl}amino)-3-nitrobenzenesulphonamide bis(hydrochloride) 0 Same procedure as in step b of the Yay example Elemental microanalysis: a Example YY + N-{[(4aS)-3-([1,1'-Biphenyl]-2-ylmethyl)-2,3,4,4a,5,6-hexahydro- 1 H-pyrazino [1,2- 1t

B” 9 — ‎aJquinolin-8-yl]carbonyl}-4-({(1R)-3-dimethylamino)-1-[(phenylsulphanyl ( methyl]propyl}amino)-3-nitrobenzenesulphonamide tris(hydrochloride) Step A: N-{[(4aS)-3-([1,1'-Biphenyl]-2-ylmethyl)-2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2] - aJquinolin-8-yl]carbonyl}-4-({(1R)-3-(dimethylamino)- 1-[(phenylsulphanyl) 2 methyl]propyl}amino)-3-nitrobenzenesulphonamide Same procedure as mentioned In step A of Example No. (0) with the replacement of the compound obtained in preparation method 1 with the compound obtained in preparation method Ne step B: : N-{[(4aS)-3-) [1,1'-Biphenyl]-2-ylmethyl)-2,3,4,4a,5,6-hexahydro-1H-pyrazino[ 1,2- Ve aJquinolin-8-yljcarbonyl}-4-({ (1R)-3-(dimethylamino)-1- [(phenylsulphanyl)methyl]propyl } amino)-3-nitrobenzenesulphonamide tris(hydrochloride) breath | To perform in step b of example number XY Vo elemental microanalysis: on mle a as

Example #YY: N-{[(4aR)-3-([1,1'-Biphenyl}-2-ylmethyl)-2,3,4,4a,5,6-hexahydro-1H-pyrazino[ 1,2- a]quinolin-8-yl]carbonyl}-4-({(1R)-3-(dimethylamino)-1-[(phenylsulphanyl)methyl] propyl } amino)-3-nitrobenzene- sulphonamide bis(hydrochloride) © Step A: N-{[(4aR)-3-([1,1'-Biphenyl]}-2-ylmethyl)-2,3,4,4a,5,6-hexahydro -1H-pyrazino[ 1,2- a]quinolin-8-yljcarbonyl)-4-({(1R)-3-(dimethylamino)-1-[(phenylsulphanyl) methyl] propyl }amino)-3 -nitrobenzenesulphonamide Same procedure as in Step A of Example No. aso) Substituting compound 0 obtained in preparation method 1 with the compound obtained in preparation No step b: N-{ [(4aR)-3-([1,1'-Biphenyl]-2-ylmethyl)-2,3,4,4a,5,6-hexahydro-1H-pyrazino[ 1,2- a]quinolin- 8-yljcarbonyl}-4-({(1R)-3-(dimethylamino)-1- [(phenylsulphanyl)methyl]propyl}amino)-3-nitrobenzenesulphonamide Yo bis(hydrochloride) Same procedure as in Step b of Example No. ?. Elemental microanalysis: ‎Yay

q A — — as) aw] ow] rel Example #1 N-{[(4aS,R)-3-[1,1'-Biphenyl]-2-ylsulphonyl)-2,3 ,4,4a,5,6-hexahydro-1H-pyrazino[1,2- a]quinolin-8-yl]carbonyl}-3-nitro-4-{[2-(phenyl-sulphanyl) ethylJamino} 8 benzenesulphonamide (same procedure as in Step A of Example 6) with the substitution of a compound in preparation method 1 for the compound in preparation method 1; And with the replacement of: 4-({(1R)-3-(dimethylamino)-1-[(phenylsulphanyl)methyl]propyl } amino)-3- nitrobenzenesulphonamide Ve using: .3-nitro-4-{[ 2-(phenylsulfanyl)ethyl]amino [ benzenesulphonamide Elemental microanalysis:

Agha Hq | loo Follow example number: Yo

N-({(4aS,R)-3-[(4'-Chloro-[1,1'-biphenyl]-2-yl)methyl]-2,3,4,4a,5,6-hexahydro-1H - pyrazino[ 1,2-a]quinolin-8-yl}carbonyl)-4-((1R)-3-(dimethylamino)-1- [(phenylsulphanyl)methyl]propyl}-3,4-dihydro-2H- 1,2,4-benzothiadiazine-7- 2 sulphonamide 1,1-dioxide Same procedure as in Step A of Example 1; with the substitution: 4-({(1R)-3-(dimethylamino)-1-[ (phenylsulphanyl)methyl]propyl}amino)-3- nitrobenzenesulphonamide using 01 4-{(1R)-3-(dimethylamino)-1-[(phenylsulphanyl)methyl]propyl}-3,4-dihydro -2H-1,2,4-benzo-thiadiazine-7-sulphonamide 1,1-dioxide.

~ Yes — : 1 example number

N-({(4aS,R)-3-[(4'-Chloro-[1,1'-biphenyl]-2-yl)methyl]-2,3,4,4a,5,6-hexahydro-1H - pyrazino[1,2-a]quinolin-8-yl}carbonyl)-4-{(1R)-3-(dimethylamino)-1- [(phenylsulphanyl)methyljpropyl}-4H-1,2,4-benzothiadiazine- 7-sulphonamide 1,1- dioxide ° Same procedure as in Step A of Example 1; with the substitution: 4-({(1R)-3-(dimethylamino)-1-[(phenylsulfanyl)methyl]propyl } amino )-3- nitrobenzenesulphonamide by . 4-{(1R)-3-(dimethylamino)-1-{(phenylsulphanyl)methyl}propyl}-4H-1,2,4- Ve benzothiadiazine-7-sulphonamide 1,1-dioxide. Example No. YY N-({(4aS,R)-3-[(4'-Chloro-[1,1'-biphenyl]-2-yl)methyl]-1,2,3,4,4a,5 ,6,7- octahydropyrazino[1,2-a][1]benzazepin-9-yl} carbonyl)-4-({(1R)-3-(dimethylamino)-1- [(phenylsulphanyl)methyl [propyl}amino)-3-nitrobenzenesulphonamide Yo Same procedure as in Step A of Example No. 1; with preparation compound No. 1 replaced by preparation compound No. Afa

-10.0-: YA Example No

N-({(4aS)-3-[(4'-Chloro-[1,1'-biphenyl]-2-yl)methyl]-1,2,3,4,4a,5,6,7- octahydropyrazino [1,2-a][1]benzazepin-9-yl} carbonyl)-4-({(1R)-3 -(dimethylamino)-1- [(phenylsulphanyl)methyl]propyl}amino)-3 -nitrobenzenesulphonamide It is separated into a column. Compound 11 the mixture of enantiomers mentioned in Preparation © tar was obtained with the procedure described in step a (brain ged) given in the title by exposing the enantiomers 1 of Example 3 Example No.

N-({(4aR)-3-[(4'-Chloro-[1,1'-biphenyl]-2-yl)methyl]-1,2,3,4,4a,5,6,7- octahydropyrazino [1,2-a}{ 1 Jbenzazepin-9-yl} carbonyl)-4-({(1R)-3-(dimethylamino)-1- Ve [(phenylsulphanyl)methyl]propyl}amino)-3-nitrobenzenesulphonamide . The procedure is as in Example No. 78; using the other isoform

Ve Example No

N-({(4aS,R)-3-[(4'-Chloro-[1,1'-biphenyl]-2-yl)methyl}-1,2,3,4,4a,5,6,7 - octahydropyrazino[ 1,2-a][ 1 Jbenzazepin-9-yl} carbonyl)-4-({(1R)-3-(4-morpholinyl)-1- Vo [(phenylsulphanyl)methyl]propyl}amino)- 3-nitrobenzenesulphonamide Same procedure as in Step A of Example 10; With a compound substitution in the method: ; And with the substitution of 11 by using a compound in the preparation method, 1 preparation is taken

_ \ 0 Y — 4-({(1R)-3-(dimethylamino)-1-[(phenylsulphanyl)methyl]propyl } amino)-3- nitrobenzenesulphonamide

By : 4-({(1R)-3-(4-morpholinyl)-1-[(phenylsulphanyl)methyl]propyl } amino)-3- nitrobenzenesulphonamide. 8 Example 1: N-({3-[(4'-Chloro-[1,1'-biphenyl}-2-y)methyl]}-1,2,3,4,4a,5 ,6,7-octahydropyrazino[1,2- ‎a][1]benzazepin-9-yl}carbonyl)-4-({(1R)-3-(4-morpholinyl)-1-[(phenylsulphanyl) methyl]propyl}amino)-3-[(trifluoromethyl)sulphonyl]benzenesulphonamide 0 Same procedure as in Step A of Example 0; substituting a compound in preparation 1 with the compound in preparation fa © And with the replacement of: 4-({(1R)-3-(dimethylamino)- 1-[(phenylsulphanyl)methyl]propyl } amino)-3- nitrobenzenesulphonamide using: 4-({(1R)-3 -(4-morpholinyl)-1-[(phenylsulfanyl)methyl]propyl } amino)-3- Yo ‎[(trifluoromethyl)sulphonyl]-benzenesulphonamide.

and 1 example YY N-({(10afalpha})-2-[(4'-Chloro-{1,1'-biphenyl]-2-yl)methyl}-1,2,3,4, 10,10a- hexahydropyrazino[ 1,2-a]indol-8-yl} carbonyl)-4-({(1R)-3-(dimethylamino)-1- [(phenylsulphanyl)methyl]propyl}amino )-3-nitrobenzenesulphonamide bishydrochloride © The compound in the title was obtained according to the procedure given in Step A of Example 1; With replacement of a compound in preparation method 1 using that in preparation what elemental microanalysis: EERE Example No. YY N-({(10a[beta])-2-[(4'-Chloro- [1,1'-biphenyl]-2-yl)methyl]-1,2,3,4,10,10a- Ve hexahdropyrazino[1,2-a)indol-8-yl1} carbonyl)-4 (((1R)-3-(dimethylamino)-1- [(phenylsulphanyl)methyl]propyl}amino)-3-nitrobenzenesulphonamide bishydrochloride ([beta]=S or R) the compound given in the title was obtained According to the procedure in Step A of Example 1 Yo; With the replacement of a compound in preparation method 1 by using that in preparation method 4 elemental microanalysis:

1 0 — Cal nd we ad Example Ve 1 N-({(10afalpha])-2-[(4'-Chloro-[1,1'-biphenyi]-2-yl) methyl]-1,2,3,4,10,10a- hexahydropyrazino[1,2-a]indol-8-yl} carbonyl)-4-({(1R)-3-(4-morpholinyl)- 1- [(phenylsulphanyl)methyl]propyl}amino)-3-nitrobenzenesulphonamide bishydrochloride©rk ([alpha}=R or) Same procedure as in Step A of Example 1; with compound substitution in method of preparation 1 Using a compound in the YA preparation method and with the replacement of: 4-({(1R)-3-(dimethylamino)-1-{(phenyl sulphanyl)methyl]propyl}amino)-3- nitrobenzenesulphonamide 01 Using: 4-({(1R)-3-(4-morpholinyl)-1-[(phenylsulphanyl)methyl]propyl } amino)-3- nitrobenzenesulphonamide. Elemental microanalysis:

- 11 m a: D mae: Example No

N-({(10a[alpha])-2-[(4'-Chloro-[1,1 -biphenyl]-2-yl)methyl]-1,2,3,4,10,10a- hexahydropyrazino[1] ,2-a] indol-8-yl} carbonyl)-4-({(1 R)-3-(4-morpholinyl)-1- [(phenylsu Iphanyl)methyl]propyl}am ino)-3- e [ (trifluoromethyl)sulphonyl]benzenesulphonamide bishydrochloride ([alpha]=R or S) 1 Substituting a compound in preparation method ae) The same procedure as in Step A of Example No.: but with the replacement of ¢ YA using the compound in method Preparation 4-({(1R)-3-(dimethylamino)-1- [(phenylsulphanyl)methyl]propyl }amino)-3- nitrobenzenesulphonamide Yo : using 4-({(1R)-3-(4) -morpholinyl)-1 -[(phenylsulfanyl)methyl propyl }amino)-3- [(triflucromethyl)sulphonyl]-benzenesu Iphonamide. Micro-elemental analysis

-111-

PY Example No

N-({3-[(4'-Chloro-[1,1'-biphenyl]-3-yl)methyl}-5-0x0-2,3,4,4a,5,6-hexahydro-1H-pyrazino [1,2-a]quinoxalin-8-yl}carbonyl)-4-(} (1R)-3-(dimethylamino)-1- [(phenylsulphanyl)methyl]propyl} amino)-3-nitrobenzenesulphonamide 8 Same procedure as mentioned In Step A of Example 1, with the replacement of a compound in preparation method 1 with the compound in preparation method 1?, then the removal step follows; Where the precipitate is separated and dissolved in a solution; titer of HCI in dioxane and after equation; The aqueous layer was extracted using CHCl, and the organic phases were collected and dried on magnesium sulphate 0; Then filtered and concentrated. The resulting precipitate was purified using (MeOH/CH2CI2) silica column chromatography to provide the expected product. Example 1? : N-({3-[(4'-Chloro-[1,1'-biphenyl]-3-yl)methyl]-2,3.4,4a,5,6-hexahydro-1H -pyrazino[ 1,2- aJquinoxalin-8-yl} carbonyl)-4-({(1R)-3-(dimethylamino)-1- [(phenylsulphanyl)methyl}propyl}amino)-3-nitrobenzenesulphonamide Vo the same procedure as in Step A of Example 10 with the substitution of a compound in preparation 1 with a compound in preparation .01 and then the stripping step follows; Where the remaining amount is isolated and dissolved in a solution; The titer of HCI in dioxane and after equation; Layer brother has been extracted

The aqueous liquids were collected using CHCl, and the organic phases were collected; And dried on magnesium sulphate ¢ and then filtered and concentrated. The resulting precipitate was purified using silica column chromatography (:146011/011:01) to provide the expected product. Example #48: N-({3-[(4-Chloro-[1,1'-biphenyl]-3-yl)methyl]-6-methyl-2,3,4,4a,5,6-hexahydro - 1 H- ° pyrazino[1,2-a]quinoxalin-8-yl} carbonyl)-4-({(1R)-3-(dimethylamino)-1- [(phenylsulphanyl)methyl]propyl} amino)-3-nitrobenzenesulphonamide | Place nitrogen at position 3 of the cyclic molecule of the compound of step H of preparation method 01 that has been deprotected with ; titer of HCI in dioxane and after equation; 0 extracted and equalized; The remaining resulting amount was subjected to the alkylation reaction AIS in the presence of methyl iodide and K2CO3. After treatment with (LIOH), it was obtained: 3-[(4'-chloro-[1,1"- biphenyl]-2-yl)methyl]-6-methyl-2,3,4,4a,5,6-hexahydro- 1 H- pyrazino[1,2-a]quinoxaline-8-carboxylic acid and this compound The latter is subjected to the step A procedure of Example 1 to obtain 0 of the compound in the title. Example 4 N-[((4aR)-3-{[2-(4-Chlorophenyl)-5,5) -dimethyl-1-cyclohexen-1 -yl}-methyl}- 2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-a]quinolin-8-yl)carbonyl}- 4-({(1 R)-2- (dimethylamino)-1-[(phenylsulphanyl)methyl]-ethyl}am ino)-3-nitrobenzene sulphonamide bishydrochloride 1 a

0 A —_ 3 —-— Same procedure as in Step A of Example 0) with the substitution of a compound in preparation 1 with a compound in preparation 1 Elemental microanalysis: Ask the © Example # €a : N-[((4aR)-3-{[2 -(4-Chlorophenyl)-5,5-dimethyl-1 -cyclohexen-1-yl}-methyl}- 2,3,4 ,4a, 5.,6-hexahydro-1 H-pyrazino[1 »2-a]quinolin-8-yl)carbonyl]-4-( {(1IR)-3-(4-morpholinyl)-1- [(phenylsu Iphanyl)methyl]-propyl } amino)-3-[ (trifluoromethyl) sulphonyl]benzenesulphonamide bishydrochloride 0 Same procedure as in step a of example number pe) Substituting a compound in preparation method 1 Using the compound given in the YY preparation method + with the replacement of: 4-({(1R)-3-(dimethylamino)-1 -[(phenylsulphanyl)methyljpropyl }amino)-3- nitrobenzenesulphonamide by 4-({( 1R)-3-(4-morphol inyl)-1 -[(phenylsulphanyl) methyl]propyl } amino)-3-[(trifluoromethyl)sulphonyl]-benzenesulphonamide.

-Quantum 1- Elemental microanalysis: re uh al f Example 1: N-[((10a[beta])-2-{[2-(4-Chlorophenyl)-5,5-dimethyl -1-cyclohexen-1-ylJmethyl} - 1,2,3,4,10,10a-hexahydropyrazinof 1,2-a]indol-8-yl)-carbonyl]-4-({ (1R)-3 -(4- 2 (ca 011101017)]-3-(f 801 morpholinyl)-1-[(phenylsulphanyl)methyl]-propyl} sulphonyl]benzenesulphonamide bishydrochloride ([beta]=S or R) same procedure mentioned in Step A of Example No. 0; with the replacement of a compound in preparation method 1 by using the compound given in preparation method “VE” and with the replacement of: 4-({(1R)-3-(dimethylamino)-1- [(phenylsulphanyl)methyl]propyl} amino)-3- AK nitrobenzenesulphonamide using: 4-({(1R)-3-(4-morpholinyl)-1-[(phenylsulphanyl)methyl]propyl } amino) -3- [(trifluoromethyl)sulphonyl]-benzenesulphonamide. Yay

Racial microanalysis: 00 |n| rs [ow [an Example No.: N-[((4aR)-3-{[4-(4-Chlorophenyl)-3 -pyridyl]methyl}-2,3,4,4a,5,6- hexahydro-1H- pyrazino[1,2-a]quinolin-8 -ylcarbonyl]-4-({(1R)-2-(dimethylam ino)-1- © [(phenylsulphanyl)methyl]ethy!} amino)-3-nitrobenzenesulphonamide trihydrochloride Same procedure as in Step A of Example 10; substituting a compound in preparation 1 with a compound in preparation Yo. Elemental microanalysis: Aaaaaaa Example Yo No.: N-[((4aR)-3-{[2-(4-Chlorophenyl)-3 -pyridyl]methyl}-2,3,4,4a,5, 6-hexahydro-1H-pyrazino[ 1,2-a]quinol in-8-yl)carbonyl]-4-({(1R)-3 -(dimethylamino)-1- [(phenylsulphanyl)methyl]propyl}am ino)-3-nitrobenzenesulphonamide

1 Same procedure as in Step A of Example 0; With the replacement of a compound in the method of preparation

At using a compound in the method of preparation, example No. M:

N-[((4aR)-3-{[3-(4-Chlorophenyl)-2-pyridylJmethyl}-2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-a]quinolin) -8-yl)carbonyl]-4-({(1R)-3-(dimethylamino)-1- 8 [(phenylsulphanyl)methyl}propyl} amino)-3-nitrobenzenesulphonamide 1 Same procedure as in Step A of Example 0) with compound substitution in the method of preparation

YY using a compound in the preparation method: Example No. 5

N-[((4aR)-3-{[3-(4-Chlorophenyl)-4-pyridylmethyl}-2,3,4,4a,5,6-hexahydro-1H-01 pyrazino[1,2-a] quinolin-8-yl)carbonyl]-4-({(1R)-3-(dimethylamino)-1- [(phenylsulphanyl)methyl]propyl}amino)-3-nitrobenzenesulphonamide 1 compound substitution in preparation ge) The same procedure mentioned in Step A of Example No

YA using a compound in the method of preparation: 4 Example No. Vo

N-({(4aR)-3-[(4-Amino-4'-chloro-[1,1"-biphenyl}-2-yl)methyl]-2,3,4,4a,5,6-hexahydro - 1H-pyrazinof1,2-a]quinolin-8-yl} carbonyl)-4-({(1R)-3-(dimethylamino)-1- [(phenylsulphanyl) methyl]propyl} amino)-3-nitrobenzenesulphonamide trihydrochloride

Yay

-11107- 1 Same procedure as in Step A of Example 1; With the replacement of a compound in the preparation method using a compound in the preparation method 3, then this is followed by the step of deprotection ¢ then the dissolution of the material and after neutralization; The dioxane layer was extracted into the remaining HCI already separated in ; caliber of and dried on organic phases using 011:01 and the organic phases were collected; Then filtered and concentrated. The resulting precipitate was purified with © magnesium sulphate to provide the expected product.

N-[((4aR)-3-{[4-(Aminomethyl)-4'-chloro-[1,1'-biphenyl]-2-ylJmethyl}-2,3,4,4a,5,6- Ve hexahydro-1H-pyrazino[1,2-a]quinolin-8-yl)carbonyl]-4-({(1R)-3-(dimethylamino)-1- [(phenylsulphanyl)methyljpropyl}amino)-3-nitrobenzenesulphonamide trihydrochloride 1 to prepare asl with a compound substitution in the +1 method from example f 2 of the a procedure given in | For the same J step, then the protection removal step follows; Then dissolve the LF material using a compound in the preparation method in 010806. And after the equation; The separated residual HCl was already extracted in ; caliber of 0; The organic phases dried the aqueous layer using 0112012, and the organic phases were collected, then filtered and concentrated. The resulting precipitate was purified ¢ magnesium sulphate on

-11”- to provide the expected product. (MeOH/CH2CI2) silica using a column chromatography: elemental microanalysis sl on a] ae on] | enn] me

DEA Example No

N-[((4aR)-3-{[3'-Fluoro-4'-chloro-[1,1'-biphenyl] -2-yl]methyl}-2,3,4,4a,5,6- hexahydro-2

IH-pyrazino[1,2-a]quinolin-8-yl)carbonyl]-4-({(1R)-3 -(dimethylamino)-1- 1 (phenylsulphanyl)methyl]propy! }amino)-3-nitrobenzenesulphonamide bishydrochloride 1 Substituting a compound in the preparation method ge) Same procedure as in Step A of Example No.

XN using a compound in the preparation method: elemental microanalysis 0 as [ow [aw [ee [0]

-1116-: 4 Example No

N-[((4aR)-3-{[4'-Cyano-[1,1'-biphenyl]-2-ylJmethyl}-2.3,4,4a,5,6-hexahydro-1H-pyrazino[1,2] -a]quinolin-8-yl)carbonyl]-4-({(1R)-3-(dimethylamino)-1- [(phenylsulphanyl) methyl]propyl} amino)-3-nitrobenzenesulphonamide bishydrochloride © with compound 1 step a In example 1; By replacing the preparation method with Jie, the procedure is the same

YY Method of preparation: microelemental analysis

On example number 1 0

N-[((4aR)-3-{[4'-(Trifluoromethyl)-[1,1'-biphenyl]-2-yl]methyl}-2,3,4,4a,5,6-hexahydro- 1H -pyrazino[1,2-a]quinolin-8-yl)carbonyl]-4-({(1R)-3-(dimethylamino)-1- [(phenylsulphanyl)methyl]propyl}amino)-3-nitrobenzenesulphonamide bishydrochloride ‏ with Compound 1 and the procedure is the same as Step A in Example 1; By replacing the compound of the method of preparation

JY Preparation Method Vo

M3 or elemental microanalysis: Example H No. N-[((4aS,R)-3-{ [4'-(Trifluoromethyl)-[1,1 -biphenyl]-2-yllmethyl}-2,3,4 ,4a,5,6- hexahydro-1H-pyrazino[ 1,2-a]quinolin- 8-yhcarbonyl]-4-({(1R)-3-(dimethylamino)-1- 5 [( phenylsulphanyl)methyl]propyl}am ino)-3-nitrobenzenesulphonamide trifluoroacetate and the action is “fie” example “On” by replacing: methyl (4aR)-2,3,4,4a,5,6-hexahydro-1 H- pyrazino[1 »2-a]quinoline-8-carboxylate (step a of preparation method (YF) with mixture: methyl (4aS,R)-2,3,4,4a,5,6-hexahydro-1H -pyrazino[1 ,2-a]quinoline-8-carboxylate Ve (Step C of preparation method 1). Example No. ht N-({(4aR)-3-[2~(1,3) -Benzodioxol-5-yl)benzyl]-2,3 :4,4a,5,6-hexahydro-1 H-pyrazino[1,2- ajquinolin-8-yl} carbonyl)-4-({(1R) )-3 -(dimethylamino)-1 -[(phenylsulphanyl)methyl] propyl } amino)-3-nitrobenzenesulphonamide bishydrochloride Vo

y = by compound 1 and the procedure is the same as Step A in Example 1; By replacing the compound of the method of preparation

Ye Preparation method: elemental microanalysis uh qa xe: ov Example No. 2

N-({(4aS,R)-3-[2-(1,3-Benzodioxol-5-yl)benzyl]-2,3,4,4a,5,6-hexahydro-1H-pyrazino[ 1,2 -a]quinolin-8-yl} carbonyl-4-{[2-(phenylsulphanyl)ethyl]-amino} )-3- nitrobenzenesulphonamide trifluoroacetate : by replacing the example of Jie with the procedure being methyl (4aR)-2 ,3,4,4a,5,6-hexahydro- 1 H-pyrazino[ 1,2-a]quinoline-8-carboxylate Ve : in mixture (YY) (Step A of preparation method) methyl (4aS,R) -2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-a]quinoline-8-carboxylate : (step h of method of preparation \ ( ' and using

1 1 7 —_ _ 4-{[2-(phenylsulphanyl)ethyl]Jamino} 3-nitrobenzenesulphonamide instead of 4-({(1R)-3- (dimethylamino)-1-[(phenylsulphanyl)methyl [propyl}amino)-3- nitrobenzenesulphonamide. -Benzhydryl-2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-a]quinolin-8- ylJcarbonyl}-4-({(1R)-3-(dimethylamino)- 1- [(phenyl-sulphanyl)methyl]propyl} amino)- 3-nitrobenzenesulphonamide 0 The procedure is the same as Jie Step A in Example 1; by replacing the method compound 1 with the method compound YO Knicks

-11/-: Accurate racial analysis

EET G7 y 100 Example No

N-[((4aR)-3-{2-Bromobenzyl}-2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-a]quinolin-8- yhcarbonyl]-4-( {(1R)-3-(dimethylamino)-1-[(phenyl-sulphanyl)methyl]propylJamino)-3- 8 nitrobenzenesulphonamide bishydrochloride The compound obtained in step A of preparation method 1? is subjected to a special procedure J The resulting product is then subjected to 117 of step n of the preparation method 1. of step a of example number: elemental microanalysis 0 aa 1

-114-: 1 Example No

N-[((4aS,R)-3-{2-Bromobenzyl}-2,3,4,4a,5,6-hexahydro-1H-pyrazino[ 1,2-a]quinolin-8- yl)carbonyl] -4-([2-(phenylsulphanyi)ethyl]Jamino)-3-nitrobenzenesulphonamide hydrochloride: The procedure is the same as Example 00 by replacing © methyl (4aR)-2,3,4,4a,5,6-hexahydro-1H- pyrazino[ 1,2-ajquinoline-8-carboxylate : in mixture (YF) (Step A of method of preparation) methyl (4aS,R)-2,3,4,4a,5,6-hexahydro-1H-pyrazino[ 1,2-a]quinoline-8-carboxylate: Using 1 1 (step h of the method of preparation: instead of 4-{[2-(phenylsulphanyl)ethyl]amino} 3-nitrobenzenesulphonamide Ye 4-( {(1R)-3-(dimethylamino)-1-[(phenylsulphanyl)methyl]propyl} amino)-3- nitrobenzenesulphonamide. : Elemental microanalysis Lam ge

Yay

— 3Y. — : E1 Example No

N-({(4aR)-3-[(4'-Chloro-[1,1 “-biphenyl]-2-yl)methyl]-2,3 .4,4a,5,6-hexahydro-1H-pyrazino [1,2-a]quinolin-8-yl} carbonyl)-4-({(1R)-3 -(4-morpholinyl)-1 -[(phenyl-sulphanyl)methyl]propyl} amino)-3-nitrobenzenesulphonamide bishydrochloride with compound 1 by replacing the preparation method compound 1 with example number i step Jie and the procedure is the same © : and by replacing the preparation method VY 4-({(1R)-3-(dimethylamino) -1 -[(phenylsulfanyl)methyl]propyl } amino)-3- nitrobenzenesulphonamide . : by 4-({(1R)-3-(4-morpholinyl)-1 -[(phenylsulphanyl)methyl]propyl yamino)-3- Ve nitrobenzenesulphonamide. : elemental microanalysis ts | on [aw | language| Yay

-1171-: OA Example No

N-({(4aS,R)-3-[(4'-Chloro-[1,1"-biphenyl]-2-yl)methyl]-2,3,4,4a,5,6-hexahydro-1H - pyrazino[1,2-a]quinolin-8-yl} carbonyl)-4-({(1R)-3-(4-morpholinyl)-1- [(phenylsulphanyl) methyl]propyl}amino)-3-nitrobenzenesulphonamide bishydrochloride 2 : by substituting ov example Jia for the J procedure and is methyl (4aR)-2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-a]quinoline- 8-carboxylate : in mixture (YY) (Step A of preparation method) methyl (4aS,R)-2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-a}quinoline- 8-carboxylate (1).

YY - Example #04 : N-({(4aR)-3-[(4'-Chloro-[1,1'-biphenyl]-2-yl)methyl]-2,3,4,4a, 5,6-hexahydro-1H- pyrazino[ 1,2-a]quinolin-8-yl} carbonyl)-4-({(1R)-3-(4-morpholinyl)-1-[(phenylsulphanyl) )methyl]propyl} amino)-3-[(trifluoromethyl) sulphonyl]benzene- sulphonamide bishydrochloride © The procedure is the same as Step A in Example 1; by substituting method compound 1 with method compound VY and by substituting B : 4-({(1R)-3 -(4-morpholinyl)-1-[(phenylsulfanyl)methyl}propyl ( amino)-3- [(trifluoromethyl)sulphonyl}-benzenesulphonamide Elemental microanalysis: A

YY

: 0 Example No

N-({(4aS,R)-3-[(4'-Chloro-[1,1'-biphenyl]-2-yl)methyl]-2,3,4,4a,5,6-hexahydro-1H - pyrazino[1,2-a]quinolin-8-y1} carbonyl)-4-({(1S)-3-(4-morpholinyl)-1- [(phenylsulphanyl)methyl]propyl} amino)-3-nitrobenzenesulphonamide © bishydrochloride : by replacing 0d Jad and the procedure is like methyl (4aR)-2,3,4,4a,5,6-hexahydro-1H-pyrazino[ 1,2-a]quinoline-8-carboxylate : from Preparation method? 7) with mixture i (step methyl (4aS,R)-2,3,4,4a,5,6-hexahydro-1H-pyrazino[ 1,2-a]quinoline-8-carboxylate : And by replacing Al » ( 1 (Step H of the method of preparation Yo 4-({(1R)-3-(4-morpholinyl)-1-[(phenyl-sulphanyl)methyl]propyl} amino)-3- [ (trifluoromethyl)sulphonyl]benzenesulphonamide : elemental microanalysis

Example WY N-({(4aR)-3-[(4'-Chloro-[1,1'-biphenyl]-2-yl)methyl]-2,3,4,4a,5,6 -hexahydro-1H- pyrazino[ 1,2-a]quinolin-8-yl} carbonyl)-4-({(1R)-3-(4-methyl-1-piperazinyl)-1- [( phenylsulfanyl)methyl]propyl}amino)-3-nitrobenzenesulphonamide bishydrochloride © and the J of a procedure is the same as Jie step i in Example No. 3 by replacing the preparation method compound 1 with the preparation method compound AY and by substituting: 4- (((1R)-3-(dimethylamino)-1-[(phenylsulphanyl)methyl]propyl} amino)-3- nitrobenzenesulphonamide B: 4-({(1R)-3-(4-methyl- 1-piperazinyl)-1-[(phenylsulphanyl)methyl]propyl} amino)-3- Ve nitrobenzene-sulphonamide Example No. 11: N-({(4aR)-3-[(4'- Chloro-[1,1"-biphenyl]-2-yl)methyl]-2,3,4,4a,5,6-hexahydro-1H- pyrazino[1,2-a]quinolin-8-yl} carbonyl)-4-({(1R)-3-(1-piperidyl)-1-[ (phenyl ‎sulphanyl)methyl] propyl}amino)-3-nitrobenzenesulphonamide bishydrochloride 1 The procedure is the same as Step A in Example 1; By replacing the preparation method compound 1 with the preparation method compound VY and by replacing:

~\Yo- 4-({(1R)-3-(dimethylamino)- 1 -[(phenylsulphanyl)methylJpropyl} amino)-3- nitrobenzenesulphonamide : by 4-({(1R)-3-(1- piperidyl)-1 -[(phenylsulphanyl)methyl]propyl }amino)-3- nitrobenzenesulphonamide. 2: Micro-elemental analysis

IRENE IT

Ay Example No

N-({(4aS,R)-3-[(4'-Chloro-[1,1 “biphenyl}-2-yl)methyl]-2,3,4,4a,5,6-hexahydro- 1H- pyrazino[ 1,2-a]quinolin-8-yl} carbonyl)-4-({( IR)-3-(1-piperidyl)-1- Ye [(phenylsulphanyl)methyl]propyl} amino)-3-nitrobenzenesulphonamide bishydrochloride : by substituting YY and the procedure is like the example methyl (4aR)-2,3,4,4a,5, 6-hexahydro-1H-pyrazinof[ .2-a]quinoline-8-carboxylate : with a mixture ( YY (Step A of preparation method 0

methyl (4aS,R)-2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-a]quinoline-8-carboxylate (Step H of Preparation Method 1). Analysis Elemental Flour: Milled by EEE 5 Example No. Ne

N-({(4aS,R)-3-[(4'-Chloro-[1,1'-biphenyl]-2-yl)methyl]-2,3,4,4a,5,6-hexahydro-1H - pyrazino[ 1,2-a]quinolin-8-yl} carbonyl)-4-({(1S)-3-(1-piperidyl)-1- [(phenylsulphanyl)methyl]propyl} amino)-3-nitrobenzenesulphonamide bishydrochloride : by replacing AF with example Jie and the action is 0 4-({(1R)-3-(1-piperidyl)-1-[(phenylsulphanyl)methyl propyl} amino)-3- nitrobenzenesulphonamide 4-({ (1S)-3-(1-piperidy!)-1-[(phenylsulphanyl)methyl]propyl} amino)-3- nitrobenzenesulphonamide Vo

Yay

Sala 1 Y _ Elemental microanalysis: Sunn fae n Sunn A Example number of: N-({(4aR)-3-[(4'-Chloro-[1,1'-biphenyl]- 2-yl)methyl]-2,3,4,4a,5,6-hexahydro-1H- pyrazino[1,2-a]quinolin-8-yl} carbonyl)-4-({(1R)- 3-(1-pyrrolidinyl)-1- 2 [(phenylsulphanyl)methyl]propyl}amino)-3-nitrobenzenesulphonamide bishydrochloride The procedure is the same as Step A in Example 1; by replacing the compound of method 1 with the compound of method Prepare VY by substituting: 4-({(1R)-3-(dimethylamino)-1-[(phenylsulphanyl)methyl]propyl }amino)-3- nitrobenzenesulphonamide 01 Pa 4-({( 1R)-3-(1-pyrrolidinyl)- 1-[(phenylsulphanyl)methyl]propyl} amino)-3- nitrobenzenesulphonamide.

-YYA-: elemental microanalysis a for mah a: 17 example no

N-({(4aR)-3-[(4'-Chloro-[1,1 -biphenyl]-2-yl)methyl]-2,3,4,4a,5,6-hexahydro- 1H-pyrazino[ 1,2-a]quinolin-8-yl} carbonyl)-4-({(1R)-3~(3 ,6-dihydro-1(2H)-pyridyl)-1- © [(phenylsulphanyl)methyl]propyl }amino)-3-nitrobenzenesulphonamide bishydrochloride with compound 1 by replacing preparation method 0 and the procedure is the same as step A in example number: and by replacing VY preparation method 4-({(1R)-3-( dimethylamino)-1- [(phenylsulphany)methyl]propyl }amino)-3- nitrobenzenesulphonamide by 4-({(1 R)-3-(3,6-dihydro-1 (2H)-pyridyl)-1- Ve [ (phenylsulfanyl)methyl]propyl}amino)-3 -nitrobenzene-sulphonamide. Example No

N-({(4aR)-3-[(4'-Chloro-[1,1'-biphenyl] -2-yDmethyl]-2,3,4,4a,5,6-hexahydro-1H-pyrazino[1] ,2-a]quinolin-8-yl} carbonyl)-4-({(1R)-3 -(1-azepanyl)-1- [(phenylsulphanyl)methyl]propyl} amino)-3-nitrobenzenesulphonamide bishydrochloride 0

Yay

-179- with compound 1 and the procedure is the same as Step A in Example 1; By replacing the compound, method of preparation: Method of preparation A, by substituting 4-({(1R)-3-(dimethylamino)-1-[(phenylsulfanyl)methyl propyl ( amino)-3- nitrobenzenesulphonamide by 4-({(1R)- 3-(1-azepanyl)-1-[(phenylsulphanyl) methyl]propyl}amino)-3-nitrobenzenesulphonamide.°: Elemental microanalysis . . . . 7s LN ZHI 0 E : Example No. M

N-({(4aR)-3-[(4'-Chloro-[1,1'-biphenyl}-2-yl)methyl]-2,3,4,4a,5,6-hexahydro-1H-pyrazino [1,2-a]quinolin-8-yl} carbonyl)-4-({(1R)-3-((1R,5S)-3-azabicyclo[3.1.0]hex-3- Veyl)-1 -[(phenylsulphanyl)methyl]-propyl } amino)-3-nitrobenzenesulphonamide bishydrochloride with compound 1 by replacing the compound of preparation method oF and the procedure is the same as step A in Example No.: and by replacing VY of preparation method 4- (((1R)-3-(dimethylamino)-1-[(phenylsulphanyl)methyl]propyl} amino)-3- Yo nitrobenzenesulphonamide : by

M16 4-({(1R)-3-((1R,5S)-3-azabicyclo[3.1.0Thex-3-yl)-1-[(phenylsulfanyl ‎Ymethyl]propyl}amino)-3-nitrobenzenesulphonamide. Elemental microanalysis: wl a a or © The following 5" to YA examples are obtained by conjugating the tricyclic compound described in preparation method 1 with the appropriate benzenesulphonamide according to the procedure Described in Step i of Example A Example 4 N-({(4aS,R)-3-[(4'-Chloro-[1,1'-biphenyl]-2-yl)methyl} -2,3.4,4a,5,6-hexahydro- 1 H- pyrazino|1,2-a]quinolin-8-yl} carbonyl)-4-[(4-phenylbutyl)amino]-3- Yo nitrobenzenesulphonamide bistrifluoroacetate elemental microanalysis: oon Low [ee |

-191-: Example No. F

N-({(4aS,R)-3-[(4'-Chloro-[1,1'-biphenyl]-2-yl)methyl]-2,3,4,4a,5,6-hexahydro-1H -pyrazino[1,2-a]quinolin-8-yl} carbonyl)-4-{[2-(1-methyl-1H-benzimidazol-2- yhethyllamino}-3-nitrobenzenesulphonamide tristrifluoroacetate : elemental microanalysis © as [oan law te : 1/1 Example No

N-({(4aS,R)-3-[(4'-Chloro-[1,1'-biphenyl]-2-yl)methyl]-2,3,4,4a,5,6-hexahydro-1H - pyrazino{1,2-a]quinolin-8-yl} carbonyl)-4-{[2-(1H-benzimidazol-2-yl)ethyl]Jamino}-3- nitrobenzenesulphonamide tristrifluoroacetate AR Elemental microanalysis: for brother

17 - : 7 Example No

N-({(4aS.R)-3-[(4'-Chloro-[1,1'-biphenyl]-2-yl)methyl]-2,3,4,4a,5,6-hexahydro-1H -pyrazino[1,2-a]quinolin-8-yl} carbonyl)-4-[(4-phenylbutyl)amino]-3- nitrobenzenesulphonamide bistrifluoroacetate © Elemental microanalysis: SLA

VY Example No

N-({(4aS,R)-3-[(4'-Chloro-[1,1'-biphenyl]-2-yl)methyl]-2,3,4,4a,5,6-hexahydro-1H -pyrazino[1,2-a]quinolin-8-yl} carbonyl)-4-({2-[(4-methoxyphenyl) sulphanyl]ethyl} amino)-3-nitrobenzenesulphonamide trifluoroacetate Ye : Elemental microanalysis A Horizon I

Ve Example No

N-({(4aS,R)-3-[(4'-Chloro-[1,1"-biphenyl}-2-yl)methyl]-2,3,4,4a,5,6-hexahydro-1H - pyrazino[1,2-ajquinolin-8-yl} carbonyl)-4-({2-[(2-methoxyphenyl)sulphanyljethyl} Vo amino)-3-nitrobenzenesulphonamide hydrochloride

Yi4y

YY - : Elemental Microanalysis : VO Example No

N-({(4aS,R)-3-[(4'-Chloro-[1,1'-biphenyl]-2-yl)methyl]-2,3,4,4a,5,6-hexahydro-1H - pyrazino[ |,2-a]quinolin-8-yl} carbonyl)-4-({2-[(2-pyridyl)sulphanyl]ethyl} amino)-3- 5 nitrobenzenesulphonamide hydrochloride : elemental microanalysis

Cas | ax aw Goodbye: 1 Example No. '

N-({(4aS,R)-3-[(4'-Chloro-[ 1,1'-biphenyl]-2-yl)methyl]-2,3,4,4a,5,6-hexahydro-1H - 01 pyrazino[ 1,2-a]quinolin-8-yl} carbonyl)-4- {[2-(2-nitroanilino)ethyl]Jamino)-3- nitrobenzenesulphonamide hydrochloride

-16-: Accurate racial analysis «Qaf» | And ETE Example No. with a solution

N-({(4aS,R)-3-[(4'-Chloro-{1,1'-biphenyl]-2-yl)methyl]-2,3,4,4a,5,6-hexahydro-1H - pyrazino[ 1,2-ajquinolin-8-yl)carbonyl)-4-[(2-{[2-(hydroxymethyl)phenyl]sulphanyl} 5 ethyl)amino]-3-nitro-benzenesulphonamide hydrochloride : elemental microanalysis ah hq | | A Example No. A

N-({(4aS,R)-3-[(4'-Chloro-[1,1'-biphenyl]-2-yl)methyl]-2,3.4,4a,5,6-hexahydro-1H-01 Term absorption 1,2-a]quinolin-8-yl}carbonyl)4-({(1S,R)-3-(dimethylamino)-1- [(phenylsulphanyl)methyl]propyl}amino)-3-nitrobenzenesulphonamide

~-\Yo- : elemental microanalysis from l sa [ae DS Lome Tow] ah The following examples 79 to 90 are obtained by the conjugation of the tricyclic compound made for the procedure that Las, suitable benzenesulphonamide with compound 01 described in preparation method 1: from example i described in step 5 14a example number

N-({2-[(4'-Chloro-[1,1'-biphenyl]-2-yl)methyl]-1,2,3,4-tetrahydro-pyrazino[1,2-a]indol- 8 -yl}carbonyl)-4-({3-(4-methyl-1-piperazinyl)-1-[(phenylsulphanyl) methyl] propyl } amino)-3-nitrobenzenesulphonamide : Elemental microanalysis Yo time on ml a

-11+-

Ae Example No

N-({2-[(4'-Chloro-[1,1'-biphenyl]-2-yl)methyl]-1,2,3,4-tetrahydro-pyrazino[1,2-a]indol- 8 -yl)carbonyl)-4-{[3-(dimethylamino)-1-(2-phenylethyl)propylJamino}-3- nitrobenzenesulphonamide bishydrochloride : Elemental Microanalysis © ts | soon | aw 360000000 : 1 Example No

N-({2-[(4-Chloro-[1,1'-biphenyl]-2-yl)methyl]-1,2,3,4-tetrahydro-pyrazino[ -1,1,2-8[100] 8-yl}carbonyl)-4-({3-((3aR,6aS)-hexahydrocyclo-penta[c]pyrrol-2(1H)-yl)-1- [(phenylsulphanyl) methyl]propyl} amino) -3-nitrobenzenesulphonamide Ye bishydrochloride : elemental microanalysis except 7

-17-

TAY Example No

N-({2-[(4'-Chloro-[1,1'-biphenyl]-2-yl)methyl]-1,2,3,4-tetrahydro-pyrazino[1,2-a]indol- 8 -yl} carbonyl)-4-{[1-[(phenylsulphanyl)methyl]-3-(1-piperidyl)propyl]amino}-3- nitrobenzenesulphonamide bishydrochloride : elemental microanalysis © as ax (AY) Example No

N-({2-[(4'-Chloro-[1,1'-biphenyl]-2-yl)methyl]-1,2,3,4-tetrahydro-pyrazino[ 1,2-a}indol- 8 -yl}carbonyl)-4-{[1-[(phenylsulphanyl)methyl]-3-(1-pyrrolidinyl)propyl]amino}-3- nitrobenzenesulphonamide bishydrochloride 01 : Elemental Microanalysis Horizon ml xe

1m Example No. A

N-({2-[(4"-Chloro-[1,1'-biphenyl]-2-yl)methyl]-1,2,3 -4-tetrahydro-pyrazino[1,2-aJindol- 8-yl }carbonyl)-4-{[3-(dimethylamino)-1 -(phenoxymethyl)propyl]amino}-3- nitrobenzenesulphonamide bishydrochloride : Elemental Microanalysis ©

HNN

Ao: Example No

N-({2-[(4'-Chloro-[1,1'-biphenyl] -2-yl)methyl]-1,2,3,4-tetrahydro-pyrazino[1,2-a]indol- 8 -yl}carbonyl)-4-({3-(4-morpholinyl)-1- [(phenylsulphanyl)methyl]propyl} ami no)-3- nitrobenzenesulphonamide bishydrochloride Ye: Elemental microanalysis Maha Ha Jana [ove | aman

-9?11- Example No.: ‎N-({2-[(4'-Chloro-[1,1'-biphenyl}-2-yl)methyl]-1,2,3,4-tetrahydro-pyrazino [1,2-a]indol- 8-yl } carbonyl)-4-{[ 1-(anilinomethyl)-3-(dimethyl-amino)propylJamino}-3-nitro benzenesulphonamide bistrifluoroacetate © would like to note that Nitrogen is protected by the anilinomethyl group of benzenesulphonamide by the Boe function at the moment of the triple ring conjugation. The deacetylation step that produces the compound mentioned in the title takes place in the presence of 1p of HCI and dioxane. Elemental Microanalysis: Daa QA Clo A 1 Example No. A: N-({2-[(4-Chloro-[1,1"-biphenyl]-2-yl)methyl]-1,2, 3,4-tetrahydro-pyrazino[1,2-a}indol- 8-yl}carbonyl)-4-({3-(dimethylamino)-1-[2-(2-furyl)ethyl]propyl } amino )-3- nitrobenzenesulphonamide bihydrochloride

$1 for : racial microanalysis us| awl aw we

AA Example No

N-({2-[(4'-Chloro-[1,1'-biphenyl]-2-yl)methyl]-1,2,3,4-tetrahydro-pyrazino[1,2-a]indol- 8 -yl}carbonyl)-4-{[ 1-[(phenylsulphanyl)methyl]-3-(4-thiomorpholinyl)propyl]amino}-3- © nitrobenzenesulphonamide bishydrochloride : elemental microanalysis is |e am bye : Ad Example No

N-({2-[(4'-Chloro-[1,1'-biphenyl}-2-yl)methyl]-1,2,3,4-tetrahydro-pyrazino[ 1,2-a}indol- Yo 8-yl} carbonyl)-4-({3-[methoxy(methyl)amino]- 1-[(phenylsulphanyl) methyl}propyl}amino)-3-nitrobenzenesulphonamide hydrochloride

-Yéy -: 68 Example No

N-({2-[(4'-Chloro-[1,1"-biphenyl]-2-yl)methyl]-1 ,2,3,4-tetrahydro-pyrazino[1,2-a]indol- 8 -yl} carbonyl)-4-({3-(4,4-difluoro-1-piperidyl)-1 -[(phenylsulphanyl) methyl]propyl} amino)-3-nitrobenzenesulphonamide bishydrochloride : microanalysis es [oa ow [re [ : 1 example number

N-[((4aS,R)-3-{[4-(4-Chlorophenyl)-3 -pyridylJmethyl}-2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-a] [quinolin-8-yl)carbonyl]-4-{[2 -(phenyl-sulphanyl)ethylJamino}-3- nitrobenzenesulphonamide hydrochloride Ye with compound 1 in Example 1 by substituting the preparation method compound f for the same procedure as step J and it is: method of preparation 6 “? and by replacing 4-({(IR)-3-(dimethylamino)-1- [(phenylsulphanyl)-methyl]propyl } amino)-3-nitrobenzene 4-{[2-(phenylsulphanyl)ethyl]amino} -3-nitro -benzenesulphonamide. 0

-167-: Accurate elemental analysis according to a statement. 7 Example No

N-[((4aS,R)-3-{[2-(4-Chlorophenyl)-3-pyridyljmethyl}-2,3,4,4a,5,6-hexahydro-1H-pyrazino[ 1,2-a) [quinolin-8-yl)carbonyl]-4- {[2-(phenyl-sulphanyl)ethylJamino}-3- 5 nitrobenzenesulphonamide bistrifluoroacetate in compound 1 The procedure is the same as Step A in Example 1; By replacing the preparation method: Preparation method B and by replacing 4-({(1R)-3-(dimethylamino)-1-[(phenylsulphanyl)-methyl]propyl} amino)-3-nitrobenzene by 4-{[2- (phenylsulfanyl)ethyl]Jamino}-3-nitro-benzenesulphonamide. Ve: Microelemental Analysis A Yi4y

16: Example No

N-[((4aS.R)-3-{[2-(4-Chloropheny!)-3 -pyridyljmethyl}-2,3,4,4a,5,6-hexahydro-1H-pyrazino[ 1,2- a]quinolin-8-yl)carbonyl]-4-({(1 R)-3-(dimethylamino)-1- [(phenylsulphanyl) methyl Jpropyl} amino)-3-nitrobenzenesulphonamide trihydrochloride© with compound 1 and the procedure is It is the same as Step A in Example 1; By replacing a compound Preparation method Eva preparation method: Elemental microanalysis N ow E: 9 ¢ Example No. 01

N-[((4aS,R)-3-{[3 -(4-Chlorophenyl)-2-pyridylJmethyl} -2,3,4,4a,5,6-hexahydro-1H-pyrazino[ 1 ,2-a ]quinolin-8-yl)carbonyl]-3-nitro-4- {[2-(phenylsulphanyl) ethylJamino}benzenesulphonamide hydrochloride

-166- : Elemental microanalysis is based on Compound 1 in Example 3 by replacing the component of preparation method i step Jie and the procedure is the same: and by replacing YA preparation method 4-( {(1R)-3~(dimethylamino)-1-[(phenyisulphanyl)-methyl]propyl} amino)-3-nitrobenzene 1 by 4-{[2-(phenylsulphanyl)ethyl]amino}-3-nitro-benzenesulphonamide. 4¢: Example No

N-[((4aS,R)-3-{[3-(4-Chlorophenyl)-4-pyridyljmethyl}-2,3,4,4a,5,6-hexahydro-1H-pyrazino[ 1,2-a) ]quinolin-8-yl)carbonyl]-4- {[2-(phenylsulphanyl)ethyl}amino}-3- nitrobenzenesulphonamide bishydrochloride 01 in compound 1 Step A in Example 0; By replacing the preparation method compound, Jie, and the procedure is the same: Preparation method 4? and by replacing 4-({(1R)-3-(dimethylamino)-1-[(phenylsulphanyl)-methyl]propyl } amino)-3-nitrobenzene 4-{[2-(phenylsulphanyl)ethylJamino}-3-nitro-benzenesulphonamide : b

C-1 Elemental microanalysis: DDS A: Ta Example No.: N-[((4aS,R)-3-[(2-(4-Pyridyl)-3-pyridyl)methyl]-2, 3,4,4a,5,6-hexahydro-1H- pyrazino[ 1,2-a]quinolin-8-yl)carbonyl}-4-({(1R)-3-(dimethylamino)-1- 5 [(phenylsulphanyl)methyl]propyl}amino)-3-nitrobenzene-sulphonamide trishydrochloride The procedure is the same as Jie Step A in Example 1; by substituting the method compound 1 with the method compound LE 0 Elemental microanalysis: for Example No.: 4v N-{((4aS,R)-3-[(2-(6-Chloro-pyrid-3-yl)-3-pyridyl)methyl]- 2,3,4,4a,5,6-hexahydro-1H- pyrazino [1,2-a]quinoline-8-carbonyl]-4-({(1R)-3-(dimethylamino)-1-[ (phenylsulfanyl) methyl]propyl } amino)-3-nitrobenzenesulphonamide trishydrochloride 1

-P1- The procedure is the same as Step A in Example 1; by replacing the preparation method compound 1 with the preparation method component 41. Elemental Microanalysis: A 2 Example No. 4A: N-[((4aS,R)-3-[(2-(6-Hydroxy-pyrid-3-yl)-3-pyridyl)methyl]-2, 3.4.4a,5 ,6-hexahydro-1H- pyrazino[ 1,2-a]quinoline-8-carbonyl]-4-({(1R)-3-(dimethylamino)-1- [(phenylsulphanyl) )methyl] propyl } amino)-3-nitrobenzenesulphonamide bishydrochloride 0 The procedure is the same as Step A in Example 1; by substituting the compound of method 1 with the compound of method 47. Example 4: [N-] ((4aS,R)-2-{[2-(4-Chlorophenyl)-3-pyridyljmethyl}-1,2,3 ,4-tetrahydropyrazino[1,2- alindole-8-carbonyl]-4-( {(1R)-3-(dimethylamino)-1-[(phenyl sulphanyl)methyl] propyl}amino)-3-nitrobenzenesulphonamide bishydrochloride Yo Yi4qy

-/A61- The procedure is the same as step A in Example No. 1; by replacing the compound of the preparation method 1 with the compound of the preparation method LY Elemental microanalysis: Except the six for 2 Example No. ve \: N- [((4aS,R)-2-{[2-(6-Chloro-pyrid-3-yl)-3-pyridylJmethyl}-1,2,3,4-tetrahydro-pyrazino[ 1,2-a ]indole-8-carbonyl]-4-({(1R)-3-(dimethyl-amino)-1-[(phenyl ‎sulphanyl)methyl]propyl} amino)-3-nitrobenzene-sulphonamide bishydrochloride and the procedure is Same as Step A in Example 1; by replacing the compound of preparation 1 with compound 01 of preparation. + Example No. Ned N-[((4aS,R)-3-{[4'-Cyano-[ 1,1'-biphenyl]-2-yl]methyl}-2,3,4,4a,5,6-hexahydro-1H- pyrazino[ 1,2-a]quinolin-8-yl)carbonyl]- 4-{[2-(phenylsulphanyl)ethyl]amino}-3- nitrobenzenesulphonamide trifluoroacetate yo and is 1 for a procedure as in Example 64) by replacing: methyl (4aR)-2,3,4,4a ,5,6-hexahydro-1H-pyrazino[ 1,2-a]quinoline-8-carboxylate (step a of preparation method (YF) with mixture: methyl (4aS,R)-2,3,4,4a ,5,6-hexahydro-1H-pyrazino[1,2-a]quinoline-8-carboxylate (Step h of Preparation Method 1) and by replacing:

-11m 4-({(1R)-3-(dimethylamino)-1-[(phenylsulphanyl)-methyl]propyl} amino)-3-nitrobenzene by 4-{[2-(phenylsulphanyl)ethylJamino}- 3-nitro-benzenesulphonamide.

NY Example No

N-[((4aS,R)-3-{[4'-(Trifluoromethyl)-[1,1'-biphenyl]-2-yljmethyl}-2,3 ,4,4a,5,6- hexahydro-1H -pyrazino[ 1,2-a]quinolin-8-yl)carbonyl]-4-{[2-(phenyl- 5 sulphanyl)ethyl]Jamino}-3-nitrobenzenesulphonamide trifluoroacetate : ; by substituting 0 and the procedure is as example methyl (4aR)-2,3,4,4a,5,6-hexahydro-1H-pyrazino[ 1,2-a]quinoline-8-carboxylate : with (YY) mixture (Step A of the method of preparing methyl (4aS,R)-2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-a]quinoline-8-carboxylate Ve: by substituting 1) (Step h of preparation method 4-({(1R)-3-(dimethylamino)-1-[(phenylsulphanyl)-methyl]propyl} amino)-3-nitrobenzene 4-{[2-(phenyl sulphanyl)ethyl) ]amino}-3-nitro-benzenesulphonamide : elemental microanalysis 11 vol [iw ] 7

VY Example No

N-[((4aS,R)-3-{[3'-(Trifluoromethyl)-[1,1'-biphenyl]-2-yl]methyl}-2,3,4,4a,5,6- hexahydro - 1H-pyrazino[1,2-a]quinolin-8-yl)carbonyl]-4-{[2-(phenyl-sulphanyl)ethyl]lamino}-3-nitrobenzenesulphonamide trifluoroacetate

-1¢4~ and the J is for a procedure like Example 01 in the synthesis pathway by substituting: 4-trifluoro-methylboronic acid by 3-trifluoromethylphenylboronic acid. Example 8 Ye N-[((4aS,R) -3-{[4'-(tert-Butyl)-[1,1'"-biphenyl]-2-ylJmethyl}-2,3,4,4a,5,6-hexahydro-1H- pyrazino[ 1 ,2-aJquinolin-8-yl)carbonyl]-4-{[2-(phenylsulphanyl)ethyl]-amino}-3- 5 nitrobenzenesulphonamide trifluoroacetate The preparation compound £0 is subjected to the procedure for Step A of Example 1; by replacing -4 (((1R)-3-(dimethylamino)-1-[(phenylsulphanyl)methyl]propyl } amino)-3-nitro-benzene with 4-{[2-(phenylsulphanyl)ethyl]Jamino }-3-nitrobenzenesulphonamide. '-biphenyl]-2-ylJmethyl}-2,3,4,4a,5,6-hexahydro-1H- pyrazino[ 1,2-a]quinolin-8-yl)carbonyl]-4-{[2 -(phenylsulfanyl)ethyl]-amino}-3- nitrobenzenesulphonamide trifluoroacetate \o

— 1 dom : in the preparation method © by replacing the ARR: Example No. Jia and the a for the procedure is 0 3,5-dimethylphenylboronic acid b 4-tert-butylphenylboronic acid : elemental microanalysis elo Lae lee]

NE Example ©

N-[((4aS,R)-3-{[2',4'-Dimethoxy-[1,1'-biphenyl]-2-yl methyl }-2,3,4,4a,5,6-hexahydro - 1 H-pyrazino[ 1,2-a]quinolin-8-yl)carbonyl]-4-{ [2-(phenyl-sulphanyl)ethyl]amino}-3- nitrobenzenesulphonamide trifluoroacetate: In the preparation method, replace Vo f for a procedure such as Example No. . 2,4-dimethoxyphenylboronic acid 4-tert-butylphenylboronic acid Ve : Elemental microanalysis z os Loan [am [ae [ on | Ah Tene [one [mp

Yiqy

- 11 -

Yay example number

N-[((4aS,R)-3-{[3',4'-Dimethoxy-[1,1"-biphenyl]-2-ylimethyl}-2,3,4,4a,5,6-hexahydro- 1H-pyrazino[1,2-a]quinolin-8-yl)carbonyl]-4-{[2 -(phenyl-sulphanyl)ethyl]Jamino}-3- nitrobenzenesulphonamide trifluoroacetate: by substituting to and the procedure is like an example L in preparation method © 0 3,4-dimethoxyphenylboronic acid 4-tert-butylphenylboronic acid : elemental microanalysis as [ow [aw [ae [0]

Ye A Example No

N-[((4aS,R)-3-{[2',3"-Dimethoxy-[1,1 -biphenyl]-2-ylJmethyl}-2,3,4,4a,5,6-hexahydro-V

IH-pyrazino[1,2-a]quinolin-8-yl)carbonyl]-4- {[2-(phenyl-sulphanyl)ethyl]Jamino}-3- nitrobenzenesulphonamide trifluoroacetate : by replacing fo in the method of preparation Yat and be | To make an example, Example No. 0 2,3-dimethoxyphenylboronic acid with 4-tert-butylphenylboronic acid

Yi4y

1- What 7 no

Yq Example No

N-[((4aS,R)-3-{[4'-Fluoro-[1,1 -biphenyl]-2-ylJmethyl}-2,3,4,4a,5,6-hexahydro-1H-pyrazino[ 1,2-a]quinolin-8-yl)carbonyl]-4-{ [2-(phenylsulphanyl)ethyl]-amino}-3- nitrobenzenesulphonamide hydrochloride : by replacing fo in preparation method 004 Example No. Je The procedure is © . 4-fluorophenylboronic acid 4-tert-butylphenylboronic acid : elemental microanalysis

EST p | VY Example No

N-[((4aS,R)-3-{[3'-Fluoro-4'-chloro-[1,1"-biphenyl]-2-ylJmethyl}-2,3,4,4a,5,6- 1 hexahydro-1H-pyrazino[1,2-a]quinolin-8 -yl)carbonyl]-4-{[2-(phenyl-sulphanyl)ethyl]amino}-3-nitrobenzenesulphonamide trifluoroacetate: The procedure is like Example No.; 100; in the preparation method £0 by replacing 0 3-fluoro-4-chlorophenylboronic acid with 4-tert-butylphenylboronic acid

VY Example No. 0

N-[((4aS,R)-3-{[3',4-Dichloro-[1,1 -biphenyl]-2-yljmethyl}-2,3,4,4a,5,6-hexahydro-1H- pyrazino[1,2-a]quinolin-8-yl)carbonyl]-4-{[2 -(phenylsulphanyl)ethyl]-amino)-3- nitrobenzenesulphonamide trifluoroacetate

- 1: by replacing the to in the preparation method with 0. Example No. (fia) and the procedure is -3,4-dichlorophenylboronic acid 4-tert-butylphenylboronic acid

VY Example No

N-[((4aS,R)-3-{[4'-Methyl-[1,1"-biphenyl]-2-yl]methyl}-2,3 ,4,4a,5,6-hexahydro-1H - pyrazino[1,2-a]quinolin-8-yl)carbonyl]-4-{[2-(phenylsu Iphanyl)ethyl]-amino}-3- 5 nitrobenzenesulphonamide trifluoroacetate : in preparation £0 by substituting 004 The procedure is the same as Example No. 4-methylphenylboronic acid 4-tert-butylphenylboronic acid: elemental microanalysis

Ye. os [ow Law [ee] 111 : 0 Example No

N-[((4aS,R)-3-{[3'-Chloro-[1,1'-biphenyl] -2-ylJmethyl}-2,3,4,4a,5,6-hexahydro-1H-pyrazino [1,2-a]quinolin-8-yl)carbonyl]-4-{ [2-(phenylsulphanyl)ethyl]-amino}-3- nitrobenzenesulphonamide trifluoroacetate : In preparation method £0 Pastidal Yo € and it is | To do an example like #0

Dm1 - 4-tert-butylphenylboronic acid with .3-chlorophenylboronic acid Elemental microanalysis: 00 ah more general out Example No. 76: N-[((4aS,R)-3-{[3" -Fluoro-[1,1"-biphenyl]-2-ylmethyl}-2,3 44a, 5,6-hexahydro-1H- © pyrazino[1,2-a]quinolin-8-yl)carbonyl]- 4-{ [2-(phenylsulphanyl)ethyl]-amino}-3- nitrobenzenesulphonamide bistrifluoroacetate, and the J for the Jia procedure is Example No. 0. In the preparation method, £0 by replacing: 4-tert-butylphenylboronic acid With -3-fluorophenylboronic acid Vo Example No. Vo N-[((4aS,R)-3-{[3',4"-Difluoro-[1,1 -biphenyl]-2- yl]methyl}-2,3,4,4a,5 ,6-hexahydro-1H- pyrazino[1,2-a]quinolin-8-yl)carbonyl]-4-{ [2-(phenylsulphanyl)ethyl ]-amino}-3- nitrobenzenesulphonamide trifluoroacetate and is 1 for a procedure like example number AE in the preparation method go by replacing:

Mt 1 - 4-tert-butylphenylboronic acid with -3,4-difluorophenylboronic acid Elemental microanalysis: NAA Example No.: N-[(4aS,R)-3-{[3'- Chloro-4'-fluoro-[1,1 "-biphenyl]-2-yllmethyl}-2,3,4,4a, 5,6-hexahydro-© 1H-pyrazino[1,2-a]quinolin- 8-yl)carbonyl]-4- {[2-(phenyl-sulphanyl)ethyl]amino)-3- nitrobenzenesulphonamide trifluoroacetate, and J is to perform the example of Example No. 0 in the preparation method to by replacing: 4 -tert-butylphenylboronic acid with -3-chloro-4-fluorophenylboronic acid

- 151 - Example No. A:

N-((4aS,R)-{3-[2-(2,2-Difluoro-1,3 -benzodioxol-4-yl)benzyl]-2,3,4,4a,5,6-hexahydro- 1H -pyrazino[ 1,2-a]quinolin-8-yl} carbonyl)-3-nitro-4-{[2-(phenylsulphanyl)- ethylJamino} benzenesulphonamide trifluoroacetate: In the method of preparation, replace ¢Yet, and the procedure is like Example No. 2 -2,2-difluoro-1,3-benzodioxol-4-ylboronic acid with 4-tert-butylphenylboronic acid: elemental microanalysis [oslo] we] Z YA Example No. ,

N-((4aS,R)-{3-[2-(2,3-Dihydro-1 ~4-benzodioxin-6-yl)benzyl]-2,3,4,4a,5,6-hexahydro-V Ex. Jie No. The procedure is -2,3-dihydro-1,4-benzodioxin-6-ylboronic acid with 4-tert-butylphenylboronic acid

— B 0 1 T_ Example No. ARE! N-((4aS,R)-{3-[2-(1-Naphthyl)benzyl]-2,3,4,4a,5,6-hexahydro -1 H-pyrazino[1,2- a]quinolin-8-yl} carbonyl)-3-nitro-4-{ [2-(phenylsulphanyl)ethyl]- amino }benzenesulphonamide trifluoroacetate © and 1 is To perform an example example No. 0 in the oe preparation method, replace: 4-tert-butylphenylboronic acid with -1-naphthylboronic acid Elemental microanalysis: For Example No. 0: N-((4aS, R)-{3-[2-(2-Naphthyl)benzyl]-2,3,4,4a,5,6-hexahydro-1 H-pyrazino[1,2- Ve a]quinolin-8-yl } carbonyl)-3-nitro-4-{ [2-(phenylsulphanyl)ethyl]jamino} - benzenesulphonamide trifluoroacetate, and the J for example number ANE in the preparation method is £0 by replacing: 4-tert- butylphenylboronic acid with -2-naphthylboronic acid

— \ o A -— : elemental microanalysis

Cul a a a a

HARB Example No

N'-((4aS,R)-{3-[(4"-Chloro-[1,1 -biphenyl]-2-yl)methyl]-2,3 ,4,4a,5,6-hexahydro-1H - pyrazino[1,2-a]quinolin-8-yl} carbonyl)-4-[(2-phenoxyethyl)amino] -1,3-benzene- 5 disulphonamide trifluoroacetate : the procedure is the same as Step A in Example 1 by replacing 4-({(1R)-3-(dimethylamino)-1 -[(phenylsulphanyl)methyl]propyl } amino)-3- nitrobenzenesulphonamide -4-[(2-phenoxy-ethyl)-amino]-1 , 3-benzenedisulphonamide with acid 0 : elemental microanalysis os[oon[aw[re]

-Yodq-

YY Example No

N-((4aS,R)-{3-[(4'-Chloro-[1,1"-biphenyl}-2-yl)methyl]-2,3,4,4a,5,6-hexahydro-1H -pyrazinof1,2-a]quinolin-8-yl} carbonyl)-3-nitro-4- {[3-(2-0xo-1- azepanyl)propyl]amino} benzenesulphonamide bistrifluoroacetate : the procedure is the same as step a In Example 1, replace © 4-({(1R)-3-(dimethylamino)-1 -[(phenylsulphanyl)methyl]propyl } amino)-3- nitrobenzenesulphonamide -3-nitro-4-{[3-(2) Example No. -oxo0-1-azepanyl)propylJamino} benzenesulphonamide B HARA

N-{(4aS,R)-[3-([1,1"-Biphenyl]-2-ylmethyl)-2,3,4,4a, 5,6-hexahydro-1H-pyrazino[1,2- Yo a]quinolin-8-yljcarbonyl}-6-chloro-2-[2 -(phenylsulphanyl)ethyl]-3,4-dihydro-2H-1,2,4- benzothiadiazine-7-sulphonamide 1,1-dioxide trifluoroacetate : Substituting of step A with Example Jie and the procedure is the same 4-({(1R)-3-(dimethylamino)-1- [(phenylsulphanyl)methyl]propyl}amino)-3- nitrobenzenesulphonamide by 6- chloro-2-[2-(phenylsulfanyl)ethyl]-3,4-dihydro-2H- Vo 1,2,4-benzothiadiazine-7-sulphonamide 1,1-dioxide.

v1. - : Racial microanalysis es Loan [am [ae [|]] : 11 4 Example No.

N-((4aS,R)-{3-[(4'-Chloro-[1,1'-biphenyl]-2-yl)methyl]-2,3 ,4,4a,5,6-hexahydro-1H- pyrazino[1,2-a]quinolin-8-yl} carbonyl)-4-(2-phenoxyethyl)-4H-1,2,4-benzothiadiazine- 5 7-sulphonamide 1,1-dioxide trifluoroacetate : Step A by example No. 1; Substituting Jie and the procedure is the same as 4-({(1R)-3-(dimethylamino)-1 -[(phenylsulphanyl)methyl]propyl} amino)-3- nitrobenzenesulphonamide 4-(2-phenoxy-ethyl)-4H -1,2,4-benzothiadiazine-7-sulphonamide 1,1-dioxide. : acid Vo : elemental microanalysis ame]

-111-

VYo Example No

N-{(4aS.R)-[3 -(2-Benzylbenzyl)-2,3,4,4a,5, 6-hexahydro-1 H-pyrazino[1,2-a]quinolin-§-yl]carbonyl )-4-({(1R)-3 ~(dimethylamino)-1 -[(phenylsulphanyl)methyl]propyl }amino)-3- nitrobenzenesulphonamide hydrochloride : The procedure is the same as Step A in Example 0 by substituting © 3- nitro-4-{[2-(phenyl sulphanyl)ethyllamino} benzenesulphonamide : 4-({(1R)-3-(dimethylamino)-1 -[(phenylsulphanyl)methyl]propyl }amino)-3- nitrobenzenesulphonamide . : Elemental Microanalysis 0 ct | #7 | [ae]: 177 Example No

N-((4aS,R)-{3 -[2-(4-Chlorobenzyl)benzyl] -2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-aJquinolin-8- yl } carbonyl)-3-nitro-4- {[2-(phenylsu Iphanyl)ethyl]amino }- benzenesulphonamide hydrochloride Vo The procedure is the same as Step A in Example No. © by replacing the compound of the method of preparation © with a compound of 476. Method of preparation ,

-117- : Elemental Accurate Analysis os Loan [aw Jae [ er [ae [eee [rent [mae]) Example No. A:

N-((4aS,R)-{3-[2-Phenoxybenzyl]-2,3,4,4a,5, 6-hexahydro-1H-pyrazino[ 1,2-a]quinolin- 8-yl}carbonyl) -3-nitro-4-{[2-(phenylsulfanyl)ethyl]Jamino}-benzenesu Iphonamide ° hydrochloride in Compound 1 Step A of Example 1; By replacing the compound of the method of preparation, Jie, and the procedure is the same: The method of preparation is ba and by replacing, 4-({(1R)-3-(dimethylamino)-1- [(phenylsulphanyl)methyl]propyl}amino)-3- nitrobenzenesulphonamide + 3-nitro-4-{[2-(phenylsulphanyl)ethyl Jamino} benzenesulphonamide B: elemental microanalysis

Tn] nw we]

Example No.: 178- 1117-

N-((4aS,R)-{3 -[2-Phenoxybenzyl]-2,3,4,4a,5, 6-hexahydro-1 H-pyrazino[1,2-a]quinolin- 8-yI} carbonyl )-3-nitro-4-( {(1R)-3-(dimethylamino)-1-[(phenylsu Iphanyl)methyl] propyl}amino) bishydrochloride with compound 1 by replacing the compound of preparation method 1 and the procedure is The same as step A in Example No. © to prepare anil method: microelemental analysis

Cool nw 0 : 8 Example No

N-( {(4aR)-3-[(4'-Chloro-[1,1 -biphenyl}-2-yl)methyl]-2,3 -4,4a,5,6-hexahydro-1H- Ye pyrazino Example: [1,2-a]quinolin-8-yl} carbonyl)-4-{[(3R)-3-amino-4- (phenylsulphanyl)butyl]am ino}-3-nitrobenzenesulphonamide tristrifluoroacetate Jie number for the procedure 4-({(IR)-3-(dimethylamino)-1 -[(phenylsulphanyl)methy!]propyl }amino)-3- nitrobenzenesulphonamide Yo

By acid: 4-{[(3R)-3-amino-4-(phenylsulphanyl)butyl]amino}-3-nitrobenzenesu Iphonamide Elemental microanalysis: [aw [aw Jae | qt © Example No. HY. Sodium N-{(4aR)-3-[(4'-chloro-[1,1'-biphenyl]-2-yl)methyl]-2,3 ,4,4a,5,6-hexahydro-1H- pyrazino[1,2-a]quinolin-8-yl}carbonyl)-4-({(1R)-3 -(dimethylamino)-1- [(phenylsulphanyl)methyl]propyl} amino)-3- nitrobenzenesulphonamide This compound is obtained starting from a solution of the bis(hydrochloride) salt described in Example Y.

Vo and exposed to three equivalents of NaOH Pharmacological study Example A: Induction of Caspase activity (agi) in vitro This study was performed on three human tumor cell lineages: - one small cell carcinoma of the lung; 146 Ve - single semi-myeloid leukemia MVETT ala - single leukemia» 11 RS4;

DZD 4 1 _ The cell strains were cultured in an incubator at 17 C in the presence of 75 of COz. 11146 and 854:11 cells were cultured in 1640 complete RPMI medium containing 701 fetal dae serum ; And ? mM of glutamine and 50 units/ml of penicillin; 00 μg/mL streptomycin and 10 mM Hepes buffer; Vet pH© 1474:11 cells were cultured in homogeneous medium supplemented with GM-CSF at ¾ nano-fox ml. Cells are distributed on 7-well plates and exposed to test compounds for 7 hours. after that; They are collected and analyzed and the caspase enzyme activity in the cell lysis products is measured. This enzymatic assay is done by measuring the presence of the fluorolysis product - (Pharmacia) The results show that the compounds of the invention are potent inducers of cell death; It was rated 0 by measuring caspase© activity in the three tumor strains used and tested. For example, the compound shown in Example 01 exhibits activity at ? µmolar of Yorn IU in 146 cells, activity at 0.1 µM of Yorn IU in 1 7 cells, activity at 1 µM of YW on IU in 11 cells: 1654 Example B: Cytotoxicity In Vitro “Cytotoxicity studies were performed on the three tumor strains in Example A. Cells were distributed on microplates and exposed to test compounds for £A hours. After that; cell viability is determined by A test by color analysis, which is a microculture test, Tetrazolium (Cancer Res., 1987, 47, 939-942).

-117- 75); Cy 70 for example, for the example compound

RSA at * 01” 0.18 molar at 174:11 and “01” 4 e Induction of Caspase Activity In Vivo Example C: Induction of enzyme activity in the body of the organism oo? On an exogenous caspase patch model, the compounds of the invention were evaluated on the activation of H146 enzyme from NOD SCID cells subcutaneously into immunosuppressed mice (strain 11146 101 xo). Cells are cultured on the day of culture; test compounds are injected by pattern via “01” and YO after a period of water. Sixteen hours after treatment; the tumor masses are cured and the peritoneum / Tween 80 is 0 in tumor lysis products. *caspase analyzed and enzyme activity measured The results obtained show that the compounds of the invention can induce cell death in 11146 tumor strains in vivo, for example. An activation of more than 79,700 is obtained compared to the comparison sample of the compound

IY and the compound illustrated by example 01 JEL illustrated Vo

Anti-Tumour Activity In Vivo (oad) Example D: Antitumor Activity in Vivo The antitumor activity of the compounds of the invention is evaluated in an exograft model of cells of H146-small cell carcinoma of the lung

Yi4y

-11- 101 x 0 11146 cells are cultured subcutaneously in immunosuppressed fi (NOD SCID strain) between YO and 1" days after culture; when the tumor mass reaches approximately 151 mm The compounds of the invention are injected intraperitoneally (in a mixture of 80 Tween / water) every day for a period of YY days. The tumor mass is measured twice a week from the start of treatment. © The obtained results show that the compounds of the invention are able to Induction of tumor regression during treatment, eg 'administration of the compound in Example 1 at a dose of Yeo mg/kg significantly induces complete tumor regression during treatment; the effect persists for at least 56 days after the end of treatment .

Platelet Toxicity Example E: Platelet 0 and incubation PBS; The dilution is done in a citrated tube. Mouse blood 3171 is drawn into a citrated tube. TV is carried out in the presence of different concentrations of test products. after ; Hours of incubation at 0 (ball/μl) to every 00) fluorescent balls 0 μl of sample addition. makes morphometric analysis by flow cytometry; Is it possible to recognize the plates and promise No..? 0 fluorescent balls and makes it possible to determine the absolute number of platelets per microliter of analyzed blood. parallel Marking makes annexin 7 FITC and then analysis by hemocytosis; It is possible to determine the al ratio of platelets in cell death.

Example F: Pharmaceutical formulation: Tablets: A tablet containing a dose of © 03 mg of

N-({(4aR)-3-[(4"-chloro-[1,1 -biphenyl]-2-yl)methyl]-2,3,4,4a,5,6- hexahydro-1H-pyrazino[ 1,2 -a]quinolin-8-yl} carbonyl)-4-({(1 R)-3- (dimethyl-amino)-1-[(pheny! sulphanyl)methy!]propyl} amino)-3- ° nitrobenzene-sulphonamide bis(thydrochloride) 2 g 0 (Example No. 0 g 0 Tall) LS corn starch .... l mmm say gm 0 gm mt mmm mmf iscsi ........ Lactose 00 mmm mmm mmm mmm mmm mmm mmm mmm mmm mmm mmm mmm mmm mmm mmm mmm ¥ g ee... 10881165111170 stearate 1 g a AY net n](| [000101010«0«000«0«0«0 Hydroxypropylcellulose

Claims (1)

11 - - Elements of protection (I) A compound of formula 1-1 ‎Ry x ¥ A N f ( ) 0 X R ~ Y where: A 0 3 is an aromatic (heterocyclic) or non-aromatic ring of ©; or 1 or 7 ° atoms can contain 1 or 1 of the selected heteroatoms of oxygen ; 1 and sulfur and 60p11008 » and for the latter it is possible to replace the (C1-Co) alkyl v group straight or branched ¢ alg Recognizing that the A ring strung up in this way cannot have A containing a sulfur atom” or a Y oxygen atom and one of the q atoms of the ring could be a C =0 Ac gana n 0 Ye and 0 can be the same or different and have zero ¢ or 3 or Y where cd zero >n + n> 19 Ry 0 VY is aryl de sens or aryl heteroaryl « - 117. to + carbon atoms; 1 including Jia X + 101 series alkylene can be replaced; cycloalkylene de sane group ; Oxygen one or two carbon atoms 64 «SO; or group 0 heteroaryl heteroaryl arylene group ¢ arylene yo The other represents a group of formula hydrogen atom Rys Ry representing one of two groups V1 (VY ID) Rs NH YA Sy ~s0,— - R4 where: 4 «CH; The set represents 0-0 or Y - *. or a hydrogen group an atom Ry where in this case a hydrogen represents an atom Rs = 71 and 87 can be identical or different; Ry where each -CH,-NR,R', SINR ;RY; yy alkyl (C1-Cs) dc sane or hydrogen 33 and represented independently of the other components yy heteroaryl or heteroaryl « aryl substituted with one or more of the yg or ¢ groups heteroarylthio; or arylthio or ¢” heteroaryloxy or “aryloxy or Yo where: -NR oR or heterocycloalkyl YY; hydrogen 18.0 m can be selected which can be identical or different; from * yy ; aryl gia straight or alkoxy (Ci-Co) straight or branched,; or alkyl (©-©0) or yA or heteroaryl and heteroaryl aryl vq Yiqy - 171 - To * Rio and 0 can form an unsaturated or dicyclic group in which 1 can have a selected heteroatom substituting of oxygen + and nitrogen ; and sulfur; YY and it is understood that one or more atoms can represent a group 0-0; or vy can have a substitution as shown in the definition of heterocycloalkyl shown Lad below; © . or Res Rs form with the carbon atoms held by an aromatic or non-aromatic ring containing Yo + fo + cyclic atoms; and one nitrogen atom being in the para position of group M580, - it can contain - in addition to the nitrogen atom - an additional nitrogen atom TV and / or a group (SO), and the ring that is defined is This is how you replace © with the set WER ; is defined above; #4 - B includes a halogen atom or NO, or (Rg or f50,2-8; or (f©-6) straight alkyl or 0 branched or 0©-©) « «bored_straight or branched; where Ry can have any of the LER values, $Y is Gee above; £Y — and 8 represents an amino or alkyl group (Cj-Ce) straight or branched with ¥¢ optionally substituted by one or JST of halogen atoms ; £8 It is recognized that: “biphenyl sf” naphthyl i.e. phenyl ic sass Sado - go £7 - “heteroaryl” means a monocyclic or bicyclic group comprising at least one gv of aromatic moiety and containing from © to 10 atoms; It can include from 1 to ? EA selected heteroatoms of oxygen; and sulfur; 3 nitrogen ¢ eg: »; Groups: 177 - a - furan, thiophene, pyrrole, imidazoline, pyridine, quinoline, isoquinoline, 84 chroman, indole, benzothiophene, benzofuran, 1,3-benzodioxole and 2,3- 211 dihydro-1,4 -benzodioxine oy mah = heterocycloalkyl' ' means a monocyclic or dicyclic group that includes from − to 4 01 atoms; Allg can include from 1 to * selected heterocyclic atoms of oxygen 5e sulphur ¢ and nitrogen ¢ cycloalkyl' - 25 means de gana monocyclic or dicyclic include from ; to “hd 01 OY possible for aryl groups; heterocyclic aryl; 5 cycloalkyl other than the congener 4e” cycloalkyl that is defined to have a substitution of 1 to −4 selectable groups from a straight or branched (m©-,0) alkyl group having an optionally substituting 0 > by a group hydroxy or amino » or (m©-©) straight or branched alkoxy group; or hydroxy (1) ¢ or carboxy ¢ or a or amino Se cyano sl ¢ nitro » or group 1 + and>-) straight or branched polyhalo; alkoxycarbonyl and halogen atoms « arylene" - ay th and heterocyclic arylene'" 5 cycloalkylene' means; respectively; 4 group 0 aryl or heteroaryl » or WS cycloalkyl is defined by no before; You are introduced from 350 carbons of alkylene chain ¢ 1% their isomers and diastereoisomers and their salts added with a pharmaceutical grade VY Joie acid or a pharmaceutically acceptable base. TA brother Avr - - 1 "- a compound of formula (I) according to claim No. (1); where Y is the group (C=0) and its homologues, diastereoisomers « and salts Addition thereof with a pharmaceutically acceptable acid or a pharmaceutically acceptable base 7. 1 *- a compound having the formula ( ) according to claim No. (1); where “and 0 includes 1a;7 and their isomers and diastereoisomers” and salts of addition of which with Y is an ay acid or a ln base. Y or ¢SO,-CF; and their isomers and diastercoisomers “ and salts of 1 addition thereof with a pharmaceutically acceptable acid or a pharmaceutically acceptable base. -1 0 A compound of formula (I) of claim no. “(1) where XR; is Y set 1i2-212060-[1,1010©071]) optional substituted by one or more v combinations selected from amino 5 “cyano 5” halogen “and aminomethyl” trifluoromethyl 5¢; and their isomers, o-diastercoisomers and salts of addition thereof with a pharmaceutically acceptable acid or a pharmaceutically acceptable base. 1 1— Compound of formula (I) according to claim ¢(V) where Rs is the hydrogen atom 7 and its homologues, diastereoisomers ¢ and Leia addition salts with y is a pharmaceutically acceptable acid or a pharmaceutically acceptable base. 116 - - 1 “"- a compound with the formula (1) Gly of claim No. (1); where 87 represents a group: -(N,N-dimethylamino)-4-(phenylsulfanyl)- butan-3-yl Y 1 and its isomers 3 and diastereoisomers “and Leia addition salts with a pharmaceutically acceptable acid 3 or a pharmaceutically acceptable base. =A) a compound of formula (1) Gy of claim no. (1); where Ry is the : -(NR10R'10)-4-(phenylsulphanyl)-butan-3-y] Y 1 group such that Rg Rig is an unsaturated or dicyclic ¥ group of which Optional replacement of selected hetero-atoms of 0 nitrogen s “oxygen ¢, sulfur ¢ and their enantiomers and diastereoisomers °” and addition salts thereof with a pharmaceutically acceptable acid or base 1. D 1 4-compound It has the formula ( ) according to claim no. ¢(V) where 187 represents the hydrogen atom Y and its homologues and diastereoisomers and salts of addition thereof with YF a pharmaceutically acceptable acid or a pharmaceutically acceptable base. 1 0 compounds with the formula ( ) which is: N-({(4aR)-3-[(4'-chloro-[1,1'-biphenyl] -2-yl)methyl]-2,3,4 ,4a,5,6-hexahydro-1H- Y pyrazino[1,2-a]quinolin-8-yl} carbonyl)-4-({(1R)-3 ~(dimethylamino)-1-[(phenyI) - 3 sulphanyl)methyl]propyl}amino)-3-n itrobenzenesulphonamide, ¢ Y14y - 17e - N-({(10a[alpha])-2-[(4'-chloro-[1,1"-biphenyl]-2-yl)methyl]-1,2,3,4,10, 10a- ee 16270170-07/1732100]1,2-2[101001-8-271( carbonyl)-4-({(1R)-3-(dimethylami no)-1- 1 [(phenylsulphanyl)methyl) ]propyl}amino)-3-nitrobenzenesulphonamide, Vv N-({(10a[beta])-2-[(4'-chloro-[1,1"-biphenyl]-2-yl)methyl]-1,2 ,3,4,10,10a- A hexahydro-pyrazino[ 1,2-a]indol-8-yl} carbonyl)-4-({(1R)-3 -(dimethylamino)-1- 4 [(phenyl- sulphanyl)methyl]propyl}amino)-3-nitrobenzenesu Iphonamide, 001 N-({(10a[alpha])-2-[(4'-chloro-[1,1"-biphenyl]-2-yl)methyl] -1,2,3,4,10,10a- 11 hexahydro-pyrazino[1,2-a}indol-8-yl} carbonyl)-4-({(1R)-3-(4-morpholinyl)-1 - VY [(phenyl-sulphanyl)methyl]propyl}amino)-3-nitrobenzenesu Iphonamide, VY N-({(10a[alpha])-2-[(4'-chloro-[1,1'-biphenyl]-2-yl)methyl]-1,2,3,4,10,10a-hexa- Tn hydropyrazino[ 1,2-a}indol-8-y1} carbonyl)-4-({(1R)-3-(4-m orpholinyl)-1- Vo [(phenylsulphanyl)methyl]propyl} amino )-3- 1 [(trifluoromethyl)sulphonyl]benzene-sulphonamide, VY N-[((4aR)-3-{[2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohexen-1 -yljmethyl} - YA 2,3,4,4a,5,6-hexahydro-1H-pyrazino[1 ,2-a]quinolin-8-yl)carbonyl]-4-({(1R)-3- V4 (4-morpholinyl) )-1-[(phenylsulfanyl)methyl]propyl} amino)-3- Yu [(trifluoromethyl)-sulphonyl]benzenesulphonamide, 7 N-[((10a[beta])-2-{[2-(4-chlorophenyl)-5,5-d imethyl-1-cyclohexen-1- yy ylJmethyl}-1,2,3,4,10, 10a-hexahdropyrazino [1,2-a]indol-8-yl)carbonyl]-4- YY (((1R)-3-(4-morpholinyl)-1-[(phenylsu Iphanyl)methyl]propyl}amino)- 3- Ye yay - 1906 - [(trifluoromethyl)-sulphonyl]benzenesulphonamide, Yo N-[((4aR)-3-{[4-(4-chlorophenyl)-3-pyridylJmethyl}-2,3,4,4a,5,6- hexahydro-1H- Yi pyrazino[1,2-a]quinolin-8-yl)carbonyl]-4-({(1R)-2-(dimethylamino)-1- Yv [(phenylsulphanyl)methyl]ethyl} amino)- 3-nitrobenzenesulphonamide, YA N-({(4aR)-3-[(4-amino-4'-chloro-[1,1'-biphenyl]-2-yl)methyl]-2,3,4,4a, 5,6- 5 hexahydro-1H-pyrazino[ 1,2-a]quinolin-8-y1} carbonyl)-4-({(1 R)-3- Ye (dimethylamino)-1-[(phenylsulphanyl)methyl] propyl}am ino)-3-nitrobenzene- p sulphonamide, 7985 N-[((4aR)-3-{[4-(aminomethyl)-4'-chloro-[1,1"-biphenyl]-2 -yljmethyl}- vy 2,3,4,4a,5,6-hexahydro-1H-pyrazino[ 1,2-a]quinolin-8-yl)carbonyl]-4-( {(1R)-3- ve d im ethylamino)-1-[(phenylsulphanyl)methyl]propyl} amino)-3-nitrobenzene- Yo sulphonamide trihydrochloride, v1 N-[((4aR)-3-{[3'-fluoro-4'-chloro-[1 ,1"-biphenyl]-2-yl Jmethyl}-2,3,4,4a,5,6- vy hexahydro-1H-pyrazino[1,2-a]quinolin-8-yl(carbonyl]-4-( {(1R)-3- YA (dimethylamino)-1-[(phenylsulphanyl)methyl]propyl}amino)-3-nitrobenzene- v4 sulphonamide, 2 N-[((4aR)-3-{[4'-(trifluoromethy) ])-[1,1"-biphenyl]-2 -yl]methyl}-2,3.4,4a,5,6- 6 hexahydro-1H-pyrazino[1,2-a]quinolin-8-yl)carbonyl] -4-({(1R)-3-b (dimethylamino)-1-[(phenylsulphanyl)methyl]propy1} amino)-3- L nitrobenzenesulphonamide, 24 - 1/9 - N-[((4aR)-3-{[4'-cyano-[1,1'-biphenyl]-2-ylimethyl}-2,3.4,4a,5, 6-hexahydro-1H- ¢o pyrazino[1,2-a]quinolin-8-yl)carbonyl]-4-({(1R)-3~(dimethylamino)-1- £1 [(phenylsulphanyl)methyl]propyl}amino)-3- nitrobenzenesulphonamide, R-N-({(4aR)-3-[2-(1,3-benzodioxol-5-yl)benzyl}-2,3,4,4a,5,6-hexahydro-1H- pyrazino[1,2-a]quinolin-8-yl} carbonyl)-4-({(1R)-3-(dimethylamino)-1- £9 [(phenylsulphanyl)methyl]propyl} amino)-3 -nitrobenzenesulphonamide, ou N-({(4aR)-3-[(4'-chloro-[1,1'-biphenyl]-2-yl)methyl]-2,3,4,4a,5 ,6-hexahydro -1H- 21 pyrazino[1,2-a]quinolin-8-yl} carbonyl)-4-({(1R)-3 -(4-morpholinyl)-1- oy [(phenylsulphanyl)methyl]propyl}amino)-3-nitrobenzenesu Iphonamide, oy N-({(4aR)-3-[(4"-chloro-[1,1'-biphenyl] -2-yl)methyl]- 2,3,4,4a,5,6-hexahydro-1H- ot pyrazino[1,2-a]quinolin-8-yl} carbonyl)-4-({(1R)-3 -(4-morpholinyl)- 1- 00 [(phenylsulphanyl)methyl]propyl}amino)-3-[(tri fluoromethyl)sulphonyl]- 25 benzenesulphonamide, ov N-({(4aR)-3-[(4'-chloro-[1,1'-biphenyl] -2-yl)methyl]-2,3,4,4a,5 ,6-hexahydro-1H- oA pyrazino[1,2-a]quinolin-8-y1} carbonyl)-4-({(1R)- 3-(4-m ethyl-1-piperazinyl)-1-oq [(phenylsulphanyl)methyl]propyl}amino)-3 -nitrobenzenesulphonamide, 1. N-({(4aR)-3-{(4'-chloro-[1,1"-biphenyl]-2-yl)methyl]- 2,3,4,4a,5,6-hexahydro-1H- 1) pyrazino[1,2-a]quinolin-8-yl} carbonyl)-4-({(1R)-3 -(1-piperidyl) -1- TY [(phenylsulphanyl)methyl]propyl }amino)-3-nitrobenzenesu Iphonamide, 1 N-({(4aR)-3-[(4'-chloro-[1,1'-biphenyl]-2 -yl )methyl]-2,3,4.4a,5,6-hexahydro-1H- +6 - VA - pyrazino[1,2-a]quinolin-8-yl} carbonyl)-4-({(1R)-3-(1-pyrrolidinyl)-1- 10 [(phenylsulphanyl)methyl]propyl}amino)- 3-nitrobenzenesulphonamide, 13 N-({(4aR)-3-[(4'-chloro-[1,1'-biphenyl]-2-yl)methyl}-2,3,4,4a,5,6- hexahydro-1H-Vv pyrazino[1,2-a]quinolin-8-yl} carbonyl)-4-({(1R)-3-(3,6-dihydro-1(2H)-pyridyl)- TA 1- [(phenylsulfanyl)methyl}propyl}amino)-3-nitrobenzenesulphonamide, 14 N-({(4aR)-3-[(4'-chloro-[1,1'-biphenyl]-2-yl)methyl}-2 ,3,4,4a,5,6-hexahydro-1 H- Ve pyrazinof1,2-a]quinolin-8-yl} carbonyl)-4-({(1R)-3-(1-azepanyl)-1- [(phenyl-1-sulphanyl)methyl]propyl}amino)-3-nitrobenzenesulphonamide, L N-({(4aR)-3-[(4'-chloro-[1,1'-biphenyl]-2 -yl)methyl]-2,3,4,4a,5, 6-hexahydro-1H-l pyrazino[1,2-a]quinolin-8-yl} carbonyl)-4-({(1R) -3-((1R,5S)-3-azabicyclo- Ve [3.1.0Jhex-3-yl)-1-[(phenylsulphanyl)methyl]propyl} amino)-3-nitrobenzene- D sulphonamide, 77 and salts thereof added with a pharmaceutically acceptable acid or a pharmaceutically acceptable base: It is (1) of claim No. Gi (1) a compound of formula 1-1 N-({(4aR)-3-[(4"-chloro-[1,1"-biphenyl] -2-yl)methyl]-2,3,4,4a,5,6-hexahydro-1H- Y pyrazino[1,2-a]quinolin-8-yl} -carbonyl)-4-({(1R) -3 -(dimethylamino)-1- ¥ [(phenylsulphanyl)methyl]propyl}amino)-3-nitrobenzenesu Iphonamide ¢ salts of which are added with a pharmaceutically acceptable acid or pharmaceutically acceptable base. © Yay - 1179 - : be (1) of claim number Gy (I) a compound of formula -1" 1 N-({(4aR)-3-[(4'-chloro-[1,1'- biphenyl]-2-yl)methyl]-2,3,4,4a,5,6-hexahydro-1H- Y pyrazino[1,2-a]quinolin-8-yl} -carbonyl)-4-({( 1R)-3-(dimethylamino)-1- 3 [(phenylsulphanyl)methyl]propyl}amino)-3-nitrobenzenesulphonamide ¢ bis(thydrochloride).2 : is (1) a compound of formula (1) according to of claim VF 1 sodium N-({(4aR)-3-[(4'-chloro-[1,1'-biphenyl]-2-yl)methyl]-2,3,4,4a,5, 6- Y hexahydro-1H-pyrazino[ 1,2-a]quinolin-8-yl} -carbonyl)-4-({(1R)-3- Y (dimethylamino)-1-[(phenylsulphanyl)methyl]propyl } amino)-3- ¢ nitrobenzenesu Iphonamide ° A process for preparing a compound of formula ( ); characterized by the use of a compound of formula 1 — 4 : as a starting material Led (10D) 011 AH Cy Cl (IV) of the formula ° YH Ya. — - Ivy. A N 1 and J ( “SN 1 Rs ~ GSR 5 ny ng XA Cam - » as expressed for form I) and the set ©-7- is connected in Position la 5 of the three-cyclic system (ca) q where the compound of formula (11) ' is condensed in a basic medium in the presence or absence of coupling 1 +6 with a compound of formula (V) : (V) - 11 > HN 2 SO, Ry Y where “8 is as defined for the formula ([); VY to obtain a compound of formula ( VD) .(VD 0 XX Cy NH | Z ' Ny” <> 29 YAN = - V0 where (Y 5 “Cy and 18 are as defined by” 11 which is condensed to a compound of formula 11018787 where Ry and 1875 are as defined by 1” with respect to the formula ( I) for a compound of formula (1/8); which is a special case of VA (compound of formula HI) (I/a) Babel NN Ya Cys oo NH_ J Ry Yo where Cy is nor; 5 Ry RY and 87a are as defined before; “1 which hy can be purified by a conventional separation technique; which if desired yy is converted to die-add salts using a pharmaceutically acceptable acid or a pharmaceutically acceptable base TT and which optionally can be separated into Its isomers By for a conventional separation technique. Y¢ -11-1 A process for preparing a compound of formula (1) is characterized by the use of a compound of formula (111) in which as a prefix: v (11h cy” on v 4 where 7 is the same with respect to the formula Cy 5 (I) represents a combined three-ring system of (IV) The formula ° YAY ~ = b Iv) + A N J nw ( UN 1 Rs ~ v where ns ns RP (Xs eA) is as it stands for ( 1); the -Y-OH A group is conjugated at position E or 5 of the exempted three-cyclic system 9 3) The compound of formula (111); The form (VI) (VII) Rs Rg oy HN < 5 so; 2 yy where Rs Ry is the same as before for the form (I ) yy so as to obtain a compound of formula (1); which can be purified according to a conventional separation technique; yg and which, if desired, is converted to salts of addition thereof using a pharmaceutically acceptable acid yo or a pharmaceutically acceptable base, which can optionally be separated into its yy isomers according to a conventional separation technique. YAY - - Protection No. (1) to No. (V7) or an addition salt thereof with a pharmaceutically acceptable acid or a pharmaceutically acceptable 7 base in combination with one or more pharmaceutically acceptable excipients ¢ V. 1 — Pharmaceutical composition according to claim No. (V1) for use in the manufacture of drugs in Y as a pro-cell death alge. Y for use in the treatment of cancers 0 cancers 1 14— a pharmaceutical composition according to Claim No. (V1) for use in the manufacture of drugs for use in the treatment of cancers of the bladder ¢ and the brain “ And the breast ¢ and the uterus uterus; chronic lymphoid leukemias ¢ leukaemias – colon cancers of the colon – the esophagus and liver – o and lymphoblastic leukemia diseases leukaemias ¢ and follicular lymphomas 1 “what are melanomas; malignant haemopathies” and “myelomas” and “ovarian cancers A” and non-small cell lung cancers non-small-cell lung 5 » and prostate cancers » and 0 small-cell lung cancers -01 0 1 combination of a compound of formula (I) according to any of Claims No. (1) to No. Y (”= anti-cancer agent selected from: genotoxic agents” and Y-related toxins mitotic ¢ and anti-metabolite agents; protease inhibitors; ¢ and kinase inhibitors - -71 1 Use of a combination according to claim number (0) Y in the manufacture of drugs for use in the treatment of cancer diseases Y cancers YY 1 = Use of a compound of formula (I) according to any of the claims (1) to S(O)Y in combination with radiotherapy in the treatment of al yl cancers .Yiay